GABRB2: Difference between revisions
Content deleted Content added
replaced manual with automatic section heading levels; removed further reading citations (enough already in line) |
consistent citation formatting |
||
| Line 1: | Line 1: | ||
{{Infobox_gene}} |
{{Infobox_gene}} |
||
The '''GABAA beta-2''' subunit is a [[protein]] that in humans is encoded by the GABRB2 [[gene]]. It combines with other subunits to form the ionotropic GABAA receptors. GABA (γ-aminobutyric acid) system is the major inhibitory system in the brain, and its dominant GABAA receptor subtype is composed of α1, β2, and γ2 subunits with the stoichiometry of 2:2:1, which accounts for 43% of all GABAA receptors<ref>{{cite journal | |
The '''GABAA beta-2''' subunit is a [[protein]] that in humans is encoded by the GABRB2 [[gene]]. It combines with other subunits to form the ionotropic GABAA receptors. GABA (γ-aminobutyric acid) system is the major inhibitory system in the brain, and its dominant GABAA receptor subtype is composed of α1, β2, and γ2 subunits with the stoichiometry of 2:2:1, which accounts for 43% of all GABAA receptors<ref>{{cite journal | vauthors = McKernan RM, Whiting PJ | title = Which GABAA-receptor subtypes really occur in the brain? | journal = Trends in Neurosciences | volume = 19 | issue = 4 | pages = 139–43 | date = April 1996 | pmid = 8658597 | doi = 10.1016/s0166-2236(96)80023-3 }}</ref><ref>{{cite journal | vauthors = McCracken ML, Borghese CM, Trudell JR, Harris RA | title = A transmembrane amino acid in the GABAA receptor β2 subunit critical for the actions of alcohols and anesthetics | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 335 | issue = 3 | pages = 600–6 | date = December 2010 | pmid = 20826568 | doi = 10.1124/jpet.110.170472 }}</ref> |
||
Alternative splicing of the GABRB2 gene leads at least to four isoforms, viz. β2-long (β2L) and β2-short (β2S, β2S1, and β2S2). Alternatively spliced variants displayed similar but non-identical electrophysiological properties<ref>{{cite journal | |
Alternative splicing of the GABRB2 gene leads at least to four isoforms, viz. β2-long (β2L) and β2-short (β2S, β2S1, and β2S2). Alternatively spliced variants displayed similar but non-identical electrophysiological properties<ref>{{cite journal | vauthors = Zhao C, Xu Z, Wang F, Chen J, Ng SK, Wong PW, Yu Z, Pun FW, Ren L, Lo WS, Tsang SY, Xue H | display-authors = 6 | title = Alternative-splicing in the exon-10 region of GABA(A) receptor beta(2) subunit gene: relationships between novel isoforms and psychotic disorders | journal = PloS One | volume = 4 | issue = 9 | pages = e6977 | date = September 2009 | pmid = 19763268 | doi = 10.1371/journal.pone.0006977 }}</ref>. GABRB2 is subjected to positive selection and known to be both an alternative splicing and a recombination hotspot; it is regulated via epigenetic regulation including imprinting and gene and promoter methylation <ref>{{cite journal | vauthors = Lo WS, Xu Z, Yu Z, Pun FW, Ng SK, Chen J, Tong KL, Zhao C, Xu X, Tsang SY, Harano M, Stöber G, Nimgaonkar VL, Xue H | display-authors = 6 | title = Positive selection within the Schizophrenia-associated GABA(A) receptor beta(2) gene | journal = PloS One | volume = 2 | issue = 5 | pages = e462 | date = May 2007 | pmid = 17520021 | doi = 10.1371/journal.pone.0000462 }}</ref> <ref>{{cite journal | vauthors = Pun FW, Zhao C, Lo WS, Ng SK, Tsang SY, Nimgaonkar V, Chung WS, Ungvari GS, Xue H | display-authors = 6 | title = Imprinting in the schizophrenia candidate gene GABRB2 encoding GABA(A) receptor β(2) subunit | journal = Molecular Psychiatry | volume = 16 | issue = 5 | pages = 557–68 | date = May 2011 | pmid = 20404824 | doi = 10.1038/mp.2010.47 }}</ref><ref>{{cite journal | vauthors = Zhao C, Wang F, Pun FW, Mei L, Ren L, Yu Z, Ng SK, Chen J, Tsang SY, Xue H | display-authors = 6 | title = Epigenetic regulation on GABRB2 isoforms expression: developmental variations and disruptions in psychotic disorders | journal = Schizophrenia Research | volume = 134 | issue = 2-3 | pages = 260–6 | date = February 2012 | pmid = 22206711 | doi = 10.1016/j.schres.2011.11.029 }}</ref> |
||
GABRB2 has been associated with a number of neuropsychiatric disorders, and found to display altered expression in cancer. |
GABRB2 has been associated with a number of neuropsychiatric disorders, and found to display altered expression in cancer. |
||
== Structure == |
== Structure == |
||
GABRB2 encodes the GABAA receptor beta-2 subunit. It is highly expressed in the brain with dominance in the gray matter <ref>{{cite journal | |
GABRB2 encodes the GABAA receptor beta-2 subunit. It is highly expressed in the brain with dominance in the gray matter <ref>{{cite journal | vauthors = Zhao C, Xu Z, Chen J, Yu Z, Tong KL, Lo WS, Pun FW, Ng SK, Tsang SY, Xue H | display-authors = 6 | title = Two isoforms of GABA(A) receptor beta2 subunit with different electrophysiological properties: Differential expression and genotypical correlations in schizophrenia | journal = Molecular Psychiatry | volume = 11 | issue = 12 | pages = 1092–105 | date = December 2006 | pmid = 16983389 | doi = 10.1038/sj.mp.4001899 }}</ref>. In humans, it is located on chromosome 5q34, with 11 exons and 10 introns spanning more than 260 kb, and a promoter region ranging from 1000 bp upstream to 689 bp downstream of exon 1 <ref>{{cite web |title=GABRB2 gamma-aminobutyric acid type A receptor subunit beta2 [Homo sapiens (human)] - Gene - NCBI |url=https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=2561 |website=www.ncbi.nlm.nih.gov}}</ref>. Alternative splicing of the gene product yields at least four isoforms, viz. β2-long (β2L), β2-short (β2S) and two additional short isoforms β2S1 and β2S2. These isoforms, composed of 512, 474, 313, and 372 amino acids respectively <ref>{{cite web |title=GABRB2 - Gamma-aminobutyric acid receptor subunit beta-2 precursor - Homo sapiens (Human) - GABRB2 gene & protein |url=https://www.uniprot.org/uniprot/P47870 |website=www.uniprot.org |language=en}}</ref>, display dissimilar electrophysiological properties <ref>{{cite journal | vauthors = Zhao C, Xu Z, Chen J, Yu Z, Tong KL, Lo WS, Pun FW, Ng SK, Tsang SY, Xue H | display-authors = 6 | title = Two isoforms of GABA(A) receptor beta2 subunit with different electrophysiological properties: Differential expression and genotypical correlations in schizophrenia | journal = Molecular Psychiatry | volume = 11 | issue = 12 | pages = 1092–105 | date = December 2006 | pmid = 16983389 | doi = 10.1038/sj.mp.4001899 }}</ref>. In mice, the corresponding Gabrb2 gene on chromosome 11A5 comprises 12 exons and 11 introns, and the two isoforms β2L and β2S from alternative splicing consisted of 512 and 474 amino acids respectively <ref>{{cite web |title=Gabrb2 - Gamma-aminobutyric acid receptor subunit beta-2 precursor - Mus musculus (Mouse) - Gabrb2 gene & protein |url=https://www.uniprot.org/uniprot/P63137 |website=www.uniprot.org |language=en}}</ref>. |
||
The β-2 subunit is a component of the ligand-gated chloride GABAA receptors which belongs to the Cys-loop superfamily <ref>{{cite journal | |
The β-2 subunit is a component of the ligand-gated chloride GABAA receptors which belongs to the Cys-loop superfamily <ref>{{cite journal | vauthors = Hirose S | title = Mutant GABA(A) receptor subunits in genetic (idiopathic) epilepsy | journal = Progress in Brain Research | volume = 213 | pages = 55–85 | date = 2014 | pmid = 25194483 | doi = 10.1016/B978-0-444-63326-2.00003-X }}</ref>. Like all subunits of this family, it consists of an extracellular N-terminal domain containing a Cys-loop of 13 amino acids, four membrane-spanning domains (TM1-4) with a large intracellular loop between TM3 and TM4, and an extracellular C-terminal domain <ref>{{cite journal | vauthors = Cheng J, Ju XL, Chen XY, Liu GY | title = Homology modeling of human alpha 1 beta 2 gamma 2 and house fly beta 3 GABA receptor channels and Surflex-docking of fipronil | journal = Journal of Molecular Modeling | volume = 15 | issue = 9 | pages = 1145–53 | date = September 2009 | pmid = 19238461 | doi = 10.1007/s00894-009-0477-2 }}</ref>. Five subunits from varied families (α1-6, β1-3, γ1-3, δ, ε, π, θ, ρ1-3) combine to form the heteropentameric GABAA receptor. TM2 from each subunit participates in the formation of the ion pore of the receptor, and α2β2γ2 is the major subtype in the brain that accounts for 43% of all GABAA receptors <ref>{{cite journal | vauthors = Houston CM, Lee HH, Hosie AM, Moss SJ, Smart TG | title = Identification of the sites for CaMK-II-dependent phosphorylation of GABA(A) receptors | journal = The Journal of Biological Chemistry | volume = 282 | issue = 24 | pages = 17855–65 | date = June 2007 | pmid = 17442679 | doi = 10.1074/jbc.M611533200 }}</ref> <ref>{{cite journal | vauthors = McKernan RM, Whiting PJ | title = Which GABAA-receptor subtypes really occur in the brain? | journal = Trends in Neurosciences | volume = 19 | issue = 4 | pages = 139–43 | date = April 1996 | pmid = 8658597 | doi = 10.1016/s0166-2236(96)80023-3 }}</ref>. |
||
== Regulation == |
== Regulation == |
||
Phosphorylation is an important mechanism for the modulation of GABAA receptor function <ref>{{cite journal | |
Phosphorylation is an important mechanism for the modulation of GABAA receptor function <ref>{{cite journal | vauthors = Baumann SW, Baur R, Sigel E | title = Forced subunit assembly in alpha1beta2gamma2 GABAA receptors. Insight into the absolute arrangement | journal = The Journal of Biological Chemistry | volume = 277 | issue = 48 | pages = 46020–5 | date = November 2002 | pmid = 12324466 | doi = 10.1074/jbc.M207663200 }}</ref>.GABRB2 includes a consensus sequence for a calmodulin-dependent protein kinase II within exon 10 which is only expressed by β2L. As a result, upon repetitive stimulation, the β2L isoform-containing GABAA receptors are more vulnerable to run-down than those containing the short isoforms. Accordingly, ATP depletion reduces the inhibitory transmission of the GABAergic system due to GABAA receptors rundown through β2. Since this rundown occasioned by the presence of β2L would lead to improved maintenance of survival-favoring activities such as hunting and food gathering in the face of energy deprivation, it could be selected as an evolutionary advantage over the shorter isoforms <ref>{{cite journal | vauthors = Palma E, Ragozzino DA, Di Angelantonio S, Spinelli G, Trettel F, Martinez-Torres A, Torchia G, Arcella A, Di Gennaro G, Quarato PP, Esposito V, Cantore G, Miledi R, Eusebi F | display-authors = 6 | title = Phosphatase inhibitors remove the run-down of gamma-aminobutyric acid type A receptors in the human epileptic brain | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 27 | pages = 10183–8 | date = July 2004 | pmid = 15218107 | doi = 10.1073/pnas.0403683101 }}</ref> <ref>{{cite journal | vauthors = Lo WS, Xu Z, Yu Z, Pun FW, Ng SK, Chen J, Tong KL, Zhao C, Xu X, Tsang SY, Harano M, Stöber G, Nimgaonkar VL, Xue H | display-authors = 6 | title = Positive selection within the Schizophrenia-associated GABA(A) receptor beta(2) gene | journal = PloS One | volume = 2 | issue = 5 | pages = e462 | date = May 2007 | pmid = 17520021 | doi = 10.1371/journal.pone.0000462 }}</ref> <ref>{{cite journal | vauthors = Zhao C, Xu Z, Chen J, Yu Z, Tong KL, Lo WS, Pun FW, Ng SK, Tsang SY, Xue H | display-authors = 6 | title = Two isoforms of GABA(A) receptor beta2 subunit with different electrophysiological properties: Differential expression and genotypical correlations in schizophrenia | journal = Molecular Psychiatry | volume = 11 | issue = 12 | pages = 1092–105 | date = December 2006 | pmid = 16983389 | doi = 10.1038/sj.mp.4001899 }}</ref>. |
||
Multiple lines of evidence confirmed the epigenetic regulation of GABRB2 gene expression via methylation and imprinting. GABRB2 mRNA expression level varied with germline genotypes, and with the gender of the parent in accord with the process of imprinting <ref>{{cite journal | |
Multiple lines of evidence confirmed the epigenetic regulation of GABRB2 gene expression via methylation and imprinting. GABRB2 mRNA expression level varied with germline genotypes, and with the gender of the parent in accord with the process of imprinting <ref>{{cite journal | vauthors = Pun FW, Zhao C, Lo WS, Ng SK, Tsang SY, Nimgaonkar V, Chung WS, Ungvari GS, Xue H | display-authors = 6 | title = Imprinting in the schizophrenia candidate gene GABRB2 encoding GABA(A) receptor β(2) subunit | journal = Molecular Psychiatry | volume = 16 | issue = 5 | pages = 557–68 | date = May 2011 | pmid = 20404824 | doi = 10.1038/mp.2010.47 }}</ref> <ref>{{cite journal | vauthors = Wang L, Jiang W, Lin Q, Zhang Y, Zhao C | title = DNA methylation regulates gabrb2 mRNA expression: developmental variations and disruptions in l-methionine-induced zebrafish with schizophrenia-like symptoms | journal = Genes, Brain, and Behavior | volume = 15 | issue = 8 | pages = 702–710 | date = November 2016 | pmid = 27509263 | doi = 10.1111/gbb.12315 }}</ref> <ref>{{cite journal | vauthors = Zhao C, Wang F, Pun FW, Mei L, Ren L, Yu Z, Ng SK, Chen J, Tsang SY, Xue H | display-authors = 6 | title = Epigenetic regulation on GABRB2 isoforms expression: developmental variations and disruptions in psychotic disorders | journal = Schizophrenia Research | volume = 134 | issue = 2-3 | pages = 260–6 | date = February 2012 | pmid = 22206711 | doi = 10.1016/j.schres.2011.11.029 }}</ref> <ref>{{cite journal | vauthors = Zong L, Zhou L, Hou Y, Zhang L, Jiang W, Zhang W, Wang L, Luo X, Wang S, Deng C, Peng Z, Li S, Hu J, Zhao H, Zhao C | display-authors = 6 | title = Genetic and epigenetic regulation on the transcription of GABRB2: Genotype-dependent hydroxymethylation and methylation alterations in schizophrenia | journal = Journal of Psychiatric Research | volume = 88 | pages = 9–17 | date = May 2017 | pmid = 28063323 | doi = 10.1016/j.jpsychires.2016.12.019 }}</ref>. |
||
== Function == |
== Function == |
||
GABRB2 is highly expressed in the brain where it plays its major role <ref>{{cite journal | |
GABRB2 is highly expressed in the brain where it plays its major role <ref>{{cite journal | vauthors = Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, Habuka M, Tahmasebpoor S, Danielsson A, Edlund K, Asplund A, Sjöstedt E, Lundberg E, Szigyarto CA, Skogs M, Takanen JO, Berling H, Tegel H, Mulder J, Nilsson P, Schwenk JM, Lindskog C, Danielsson F, Mardinoglu A, Sivertsson Å, von Feilitzen K, Forsberg M, Zwahlen M, Olsson I, Navani S, Huss M, Nielsen J, Ponten F, Uhlén M | display-authors = 6 | title = Analysis of the Human Tissue-specific Expression by Genome-wide Integration of Transcriptomics and Antibody-based Proteomics | journal = Molecular & Cellular Proteomics | volume = 13 | issue = 2 | pages = 397–406 | date = February 2014 | pmid = 33498127 | doi = 10.1074/mcp.M113.035600 }}</ref>. In the immature brain, GABAA receptors participate in excitatory transmission <ref>{{cite journal | vauthors = Ben-Ari Y, Gaiarsa JL, Tyzio R, Khazipov R | title = GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations | journal = Physiological Reviews | volume = 87 | issue = 4 | pages = 1215–84 | date = October 2007 | pmid = 17928584 | doi = 10.1152/physrev.00017.2006 }}</ref>, which is important to synaptogenesis, neurogenesis, and the formation of the glutamatergic system <ref>{{cite journal | vauthors = Chen G, Trombley PQ, van den Pol AN | title = GABA receptors precede glutamate receptors in hypothalamic development; differential regulation by astrocytes | journal = Journal of Neurophysiology | volume = 74 | issue = 4 | pages = 1473–84 | date = October 1995 | pmid = 8989386 | doi = 10.1152/jn.1995.74.4.1473 }}</ref>. In the mature brain, GABAA receptors fulfill their conventional inhibitory role, with the β2 subunits participating in some of the fastest inhibitory transmissions that prevent hyperexcitability, regulate the stress response of the hypothalamic-pituitary-adrenal axis, as well as pain signals mediated by the thalamus <ref>{{cite journal | vauthors = Zhang Q, Long Q, Ott J | title = AprioriGWAS, a new pattern mining strategy for detecting genetic variants associated with disease through interaction effects | journal = PLoS Computational Biology | volume = 10 | issue = 6 | pages = e1003627 | date = June 2014 | pmid = 24901472 | doi = 10.1371/journal.pcbi.1003627 }}</ref> <ref>{{cite journal | vauthors = Herman JP, Mueller NK, Figueiredo H | title = Role of GABA and glutamate circuitry in hypothalamo-pituitary-adrenocortical stress integration | journal = Annals of the New York Academy of Sciences | volume = 1018 | issue = 1 | pages = 35–45 | date = June 2004 | pmid = 15240350 | doi = 10.1196/annals.1296.004 }}</ref>. Moreover, GABRB2 is associated with cognitive function, energy regulation, time perception <ref>{{cite journal | vauthors = Marinho V, Oliveira T, Bandeira J, Pinto GR, Gomes A, Lima V, Magalhães F, Rocha K, Ayres C, Carvalho V, Velasques B, Ribeiro P, Orsini M, Bastos VH, Gupta D, Teixeira S | display-authors = 6 | title = Genetic influence alters the brain synchronism in perception and timing | journal = Journal of Biomedical Science | volume = 25 | issue = 1 | pages = 61 | date = August 2018 | pmid = 30086746 | doi = 10.1186/s12929-018-0463-z }}</ref>, and the maintenance of efferent synaptic terminals in the mature ear <ref>{{cite journal | vauthors = Maison SF, Rosahl TW, Homanics GE, Liberman MC | title = Functional role of GABAergic innervation of the cochlea: phenotypic analysis of mice lacking GABA(A) receptor subunits alpha 1, alpha 2, alpha 5, alpha 6, beta 2, beta 3, or delta | journal = The Journal of Neuroscience | volume = 26 | issue = 40 | pages = 10315–26 | date = October 2006 | pmid = 17021187 | doi = 10.1523/JNEUROSCI.2395-06.2006 }}</ref>. |
||
== Clinical significance == |
== Clinical significance == |
||
| Line 20: | Line 20: | ||
=== Psychiatric disorders === |
=== Psychiatric disorders === |
||
==== Schizophrenia ==== |
==== Schizophrenia ==== |
||
Single nucleotide polymorphisms (SNPs) in GABRB2 were first associated with schizophrenia (SCZ) in Han Chinese, and confirmed subsequently for German, Portuguese, and Japanese SCZ patients <ref>{{cite journal | |
Single nucleotide polymorphisms (SNPs) in GABRB2 were first associated with schizophrenia (SCZ) in Han Chinese, and confirmed subsequently for German, Portuguese, and Japanese SCZ patients <ref>{{cite journal | vauthors = Lo WS, Lau CF, Xuan Z, Chan CF, Feng GY, He L, Cao ZC, Liu H, Luan QM, Xue H | display-authors = 6 | title = Association of SNPs and haplotypes in GABAA receptor beta2 gene with schizophrenia | journal = Molecular Psychiatry | volume = 9 | issue = 6 | pages = 603–8 | date = June 2004 | pmid = 14699426 | doi = 10.1038/sj.mp.4001461 }}</ref> <ref>{{cite journal | vauthors = Liu J, Shi Y, Tang W, Guo T, Li D, Yang Y, Zhao X, Wang H, Li X, Feng G, Gu N, Zhu S, Liu H, Guo Y, Shi J, Sang H, Yan L, He L | display-authors = 6 | title = Positive association of the human GABA-A-receptor beta 2 subunit gene haplotype with schizophrenia in the Chinese Han population | journal = Biochemical and Biophysical Research Communications | volume = 334 | issue = 3 | pages = 817–23 | date = September 2005 | pmid = 16023997 | doi = 10.1016/j.bbrc.2005.06.167 }}</ref> <ref>{{cite journal | vauthors = Lo WS, Harano M, Gawlik M, Yu Z, Chen J, Pun FW, Tong KL, Zhao C, Ng SK, Tsang SY, Uchimura N, Stober G, Xue H | display-authors = 6 | title = GABRB2 association with schizophrenia: commonalities and differences between ethnic groups and clinical subtypes | journal = Biological Psychiatry | volume = 61 | issue = 5 | pages = 653–60 | date = March 2007 | pmid = 16950232 | doi = 10.1016/j.biopsych.2006.05.003 }}</ref> <ref>{{cite journal | vauthors = Petryshen TL, Middleton FA, Tahl AR, Rockwell GN, Purcell S, Aldinger KA, Kirby A, Morley CP, McGann L, Gentile KL, Waggoner SG, Medeiros HM, Carvalho C, Macedo A, Albus M, Maier W, Trixler M, Eichhammer P, Schwab SG, Wildenauer DB, Azevedo MH, Pato MT, Pato CN, Daly MJ, Sklar P | display-authors = 6 | title = Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia | journal = Molecular Psychiatry | volume = 10 | issue = 12 | pages = 1074–88, 1057 | date = December 2005 | pmid = 16172613 | doi = 10.1038/sj.mp.4001739 }}</ref> <ref>{{cite journal | vauthors = Yu Z, Chen J, Shi H, Stoeber G, Tsang SY, Xue H | title = Analysis of GABRB2 association with schizophrenia in German population with DNA sequencing and one-label extension method for SNP genotyping | journal = Clinical Biochemistry | volume = 39 | issue = 3 | pages = 210–8 | date = March 2006 | pmid = 16472798 | doi = 10.1016/j.clinbiochem.2006.01.009 }}</ref>. Furthermore, their significant associations have been extended to cognitive function, psychosis, and neuroleptic-induced tardive dyskinesia in schizophrenics <ref>{{cite journal | vauthors = Tsang SY, Zhong S, Mei L, Chen J, Ng SK, Pun FW, Zhao C, Jing B, Chark R, Guo J, Tan Y, Li L, Wang C, Chew SH, Xue H | display-authors = 6 | title = Social cognitive role of schizophrenia candidate gene GABRB2 | journal = PloS One | volume = 8 | issue = 4 | pages = e62322 | date = 24 April 2013 | pmid = 23638040 | doi = 10.1371/journal.pone.0062322 }}</ref> <ref>{{cite journal | vauthors = Zhang Q, Zhang X, Song S, Wang S, Wang X, Yu H, Han H, Zhou X, Li G, Wu Y | display-authors = 6 | title = The association of GABRB2 SNPs with cognitive function in schizophrenia | journal = European Archives of Psychiatry and Clinical Neuroscience | volume = 270 | issue = 4 | pages = 443–449 | date = June 2020 | pmid = 30706170 | doi = 10.1007/s00406-019-00985-3 }}</ref> <ref>{{cite journal | vauthors = Inada T, Koga M, Ishiguro H, Horiuchi Y, Syu A, Yoshio T, Takahashi N, Ozaki N, Arinami T | display-authors = 6 | title = Pathway-based association analysis of genome-wide screening data suggest that genes associated with the gamma-aminobutyric acid receptor signaling pathway are involved in neuroleptic-induced, treatment-resistant tardive dyskinesia | journal = Pharmacogenetics and Genomics | volume = 18 | issue = 4 | pages = 317–23 | date = April 2008 | pmid = 18334916 | doi = 10.1097/FPC.0b013e3282f70492 }}</ref>. Recurrent copy number variations (CNVs) in GABRB2 were likewise associated with schizophrenia <ref>{{cite journal | vauthors = Ullah A, Long X, Mat WK, Hu T, Khan MI, Hui L, Zhang X, Sun P, Gao M, Wang J, Wang H, Li X, Sun W, Qiao M, Xue H | display-authors = 6 | title = Highly Recurrent Copy Number Variations in <i>GABRB2</i> Associated With Schizophrenia and Premenstrual Dysphoric Disorder | journal = Frontiers in Psychiatry | volume = 11 | pages = 572 | date = 30 June 2020 | pmid = 32695026 | doi = 10.3389/fpsyt.2020.00572 }}</ref>. GABRB2 expression was decreased in genotype and age-dependent manners, with reduced β2L/β2S ratios in schizophrenics serving as a key determinant of the response of receptor function to the energy status <ref>{{cite journal | vauthors = Zhao C, Xu Z, Chen J, Yu Z, Tong KL, Lo WS, Pun FW, Ng SK, Tsang SY, Xue H | display-authors = 6 | title = Two isoforms of GABA(A) receptor beta2 subunit with different electrophysiological properties: Differential expression and genotypical correlations in schizophrenia | journal = Molecular Psychiatry | volume = 11 | issue = 12 | pages = 1092–105 | date = December 2006 | pmid = 16983389 | doi = 10.1038/sj.mp.4001899 }}</ref> <ref>{{cite journal | vauthors = Lo WS, Xu Z, Yu Z, Pun FW, Ng SK, Chen J, Tong KL, Zhao C, Xu X, Tsang SY, Harano M, Stöber G, Nimgaonkar VL, Xue H | display-authors = 6 | title = Positive selection within the Schizophrenia-associated GABA(A) receptor beta(2) gene | journal = PloS One | volume = 2 | issue = 5 | pages = e462 | date = May 2007 | pmid = 17520021 | doi = 10.1371/journal.pone.0000462 }}</ref>. The regulation of its expression by methylation and imprinting <ref>{{cite journal | vauthors = Pun FW, Zhao C, Lo WS, Ng SK, Tsang SY, Nimgaonkar V, Chung WS, Ungvari GS, Xue H | display-authors = 6 | title = Imprinting in the schizophrenia candidate gene GABRB2 encoding GABA(A) receptor β(2) subunit | journal = Molecular Psychiatry | volume = 16 | issue = 5 | pages = 557–68 | date = May 2011 | pmid = 20404824 | doi = 10.1038/mp.2010.47 }}</ref> <ref>{{cite journal | vauthors = Zhao C, Wang F, Pun FW, Mei L, Ren L, Yu Z, Ng SK, Chen J, Tsang SY, Xue H | display-authors = 6 | title = Epigenetic regulation on GABRB2 isoforms expression: developmental variations and disruptions in psychotic disorders | journal = Schizophrenia Research | volume = 134 | issue = 2-3 | pages = 260–6 | date = February 2012 | pmid = 22206711 | doi = 10.1016/j.schres.2011.11.029 }}</ref> <ref>{{cite journal | vauthors = Zong L, Zhou L, Hou Y, Zhang L, Jiang W, Zhang W, Wang L, Luo X, Wang S, Deng C, Peng Z, Li S, Hu J, Zhao H, Zhao C | display-authors = 6 | title = Genetic and epigenetic regulation on the transcription of GABRB2: Genotype-dependent hydroxymethylation and methylation alterations in schizophrenia | journal = Journal of Psychiatric Research | volume = 88 | pages = 9–17 | date = May 2017 | pmid = 28063323 | doi = 10.1016/j.jpsychires.2016.12.019 }}</ref>, as well as its N-glycosylation of the β2-subunit, were altered in SCZ <ref>{{cite journal | vauthors = Mueller TM, Haroutunian V, Meador-Woodruff JH | title = N-Glycosylation of GABAA receptor subunits is altered in Schizophrenia | journal = Neuropsychopharmacology | volume = 39 | issue = 3 | pages = 528–37 | date = February 2014 | pmid = 23917429 | doi = 10.1038/npp.2013.190 }}</ref>. That GABRB2 is both a recombination hotspot and subject to positive selection could be an important factor in the widespread occurrence of SCZ <ref name="positive selection">{{cite journal | vauthors = Lo WS, Xu Z, Yu Z, Pun FW, Ng SK, Chen J, Tong KL, Zhao C, Xu X, Tsang SY, Harano M, Stöber G, Nimgaonkar VL, Xue H | display-authors = 6 | title = Positive selection within the Schizophrenia-associated GABA(A) receptor beta(2) gene | journal = PloS One | volume = 2 | issue = 5 | pages = e462 | date = May 2007 | pmid = 17520021 | doi = 10.1371/journal.pone.0000462 }}</ref>. Gabrb2-knockout mice displayed schizophrenia-like behavior including prepulse inhibition deficit and antisocial behavior that were ameliorated by the antipsychotic risperidone, strongly supporting the proposal based on postmortem SCZ brains that GABRB2 represents the key genetic factor in SCZ etiology <ref name="gabrb2 knockout">{{cite journal | vauthors = Yeung RK, Xiang ZH, Tsang SY, Li R, Ho TY, Li Q, Hui CK, Sham PC, Qiao MQ, Xue H | display-authors = 6 | title = Gabrb2-knockout mice displayed schizophrenia-like and comorbid phenotypes with interneuron-astrocyte-microglia dysregulation | journal = Translational Psychiatry | volume = 8 | issue = 1 | pages = 128 | date = July 2018 | pmid = 30013074 | doi = 10.1038/s41398-018-0176-9 }}</ref>. |
||
==== Other psychiatric disorders ==== |
==== Other psychiatric disorders ==== |
||
GABRB2 was significantly associated with bipolar disorder, with a genotype-dependent decrease in GABRB2 mRNA levels weaker than that observed in SCZ <ref name="alternative splicing">{{cite journal | |
GABRB2 was significantly associated with bipolar disorder, with a genotype-dependent decrease in GABRB2 mRNA levels weaker than that observed in SCZ <ref name="alternative splicing">{{cite journal | vauthors = Zhao C, Xu Z, Wang F, Chen J, Ng SK, Wong PW, Yu Z, Pun FW, Ren L, Lo WS, Tsang SY, Xue H | display-authors = 6 | title = Alternative-splicing in the exon-10 region of GABA(A) receptor beta(2) subunit gene: relationships between novel isoforms and psychotic disorders | journal = PloS One | volume = 4 | issue = 9 | pages = e6977 | date = September 2009 | pmid = 19763268 | doi = 10.1371/journal.pone.0006977 }}</ref> <ref>{{cite journal | vauthors = Perlis RH, Purcell S, Fagerness J, Kirby A, Petryshen TL, Fan J, Sklar P | title = Family-based association study of lithium-related and other candidate genes in bipolar disorder | journal = Archives of General Psychiatry | volume = 65 | issue = 1 | pages = 53–61 | date = January 2008 | pmid = 18180429 | doi = 10.1001/archgenpsychiatry.2007.15 }}</ref> <ref>{{cite journal | vauthors = Breuer R, Hamshere ML, Strohmaier J, Mattheisen M, Degenhardt F, Meier S, Paul T, O'Donovan MC, Mühleisen TW, Schulze TG, Nöthen MM, Cichon S, Craddock N, Rietschel M | display-authors = 6 | title = Independent evidence for the selective influence of GABA(A) receptors on one component of the bipolar disorder phenotype | journal = Molecular Psychiatry | volume = 16 | issue = 6 | pages = 587–9 | date = June 2011 | pmid = 20548298 | doi = 10.1038/mp.2010.67 }}</ref> <ref>{{cite journal | vauthors = Chen J, Tsang SY, Zhao CY, Pun FW, Yu Z, Mei L, Lo WS, Fang S, Liu H, Stöber G, Xue H | display-authors = 6 | title = GABRB2 in schizophrenia and bipolar disorder: disease association, gene expression and clinical correlations | journal = Biochemical Society Transactions | volume = 37 | issue = Pt 6 | pages = 1415–8 | date = December 2009 | pmid = 19909288 | doi = 10.1042/BST0371415 }}</ref>. In major depressive disorder, the expressions of GABAA subunit genes were altered <ref>{{cite journal | vauthors = Choudary PV, Molnar M, Evans SJ, Tomita H, Li JZ, Vawter MP, Myers RM, Bunney WE, Akil H, Watson SJ, Jones EG | display-authors = 6 | title = Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 43 | pages = 15653–8 | date = October 2005 | pmid = 16230605 | doi = 10.1073/pnas.0507901102 }}</ref>, and the expression of GABRB2 was significantly decreased in the anterior cingulate cortex, in the postmortem brains of patients <ref>{{cite journal | vauthors = Zhao J, Bao AM, Qi XR, Kamphuis W, Luchetti S, Lou JS, Swaab DF | title = Gene expression of GABA and glutamate pathway markers in the prefrontal cortex of non-suicidal elderly depressed patients | journal = Journal of Affective Disorders | volume = 138 | issue = 3 | pages = 494–502 | date = May 2012 | pmid = 22357337 | doi = 10.1016/j.jad.2012.01.013 }}</ref>. |
||
The expression of GABRB2 was significantly increased in the internet gaming disorder group, and GABRB2 was the downstream target for two circulating microRNA, viz. hsa-miR-26b-5p and hsa-miR-652-3p, which were significantly downregulated in these subjects <ref>{{cite journal | |
The expression of GABRB2 was significantly increased in the internet gaming disorder group, and GABRB2 was the downstream target for two circulating microRNA, viz. hsa-miR-26b-5p and hsa-miR-652-3p, which were significantly downregulated in these subjects <ref>{{cite journal | vauthors = Lee M, Cho H, Jung SH, Yim SH, Cho SM, Chun JW, Paik SH, Park YE, Cheon DH, Lee JE, Choi JS, Kim DJ, Chung YJ | display-authors = 6 | title = Circulating MicroRNA Expression Levels Associated With Internet Gaming Disorder | journal = Frontiers in Psychiatry | volume = 9 | pages = 81 | date = 12 March 2018 | pmid = 29593587 | doi = 10.3389/fpsyt.2018.00081 }}</ref>. |
||
The GABAergic system was suggested to be a factor in the physiopathology of premenstrual dysphoric disorder (PMDD) <ref>{{cite journal | |
The GABAergic system was suggested to be a factor in the physiopathology of premenstrual dysphoric disorder (PMDD) <ref>{{cite journal | vauthors = Hofmeister S, Bodden S | title = Premenstrual Syndrome and Premenstrual Dysphoric Disorder | journal = American Family Physician | volume = 94 | issue = 3 | pages = 236–40 | date = August 2016 | pmid = 27479626 }}</ref>. GABA levels were altered in the brain of PMDD patients <ref>{{cite journal | vauthors = Liu B, Wang G, Gao D, Gao F, Zhao B, Qiao M, Yang H, Yu Y, Ren F, Yang P, Chen W, Rae CD | display-authors = 6 | title = Alterations of GABA and glutamate-glutamine levels in premenstrual dysphoric disorder: a 3T proton magnetic resonance spectroscopy study | journal = Psychiatry Research | volume = 231 | issue = 1 | pages = 64–70 | date = January 2015 | pmid = 25465316 | doi = 10.1016/j.pscychresns.2014.10.020 }}</ref>. Two highly recurrent copy number variations in GABRB2 were associated with PMDD in Chinese and German patients, providing thereby a possible explanation of part of the complex psychological symptoms of PMDD <ref>{{cite journal | vauthors = Ullah A, Long X, Mat WK, Hu T, Khan MI, Hui L, Zhang X, Sun P, Gao M, Wang J, Wang H, Li X, Sun W, Qiao M, Xue H | display-authors = 6 | title = Highly Recurrent Copy Number Variations in <i>GABRB2</i> Associated With Schizophrenia and Premenstrual Dysphoric Disorder | journal = Frontiers in Psychiatry | volume = 11 | pages = 572 | date = 30 June 2020 | pmid = 32695026 | doi = 10.3389/fpsyt.2020.00572 }}</ref>. |
||
=== Drug dependence === |
=== Drug dependence === |
||
SNPs in GABRB2 were significantly associated with alcohol dependence and consumption in Southwestern Native Americans, Finnish, Scottish, and Sidney populations <ref>{{cite journal | |
SNPs in GABRB2 were significantly associated with alcohol dependence and consumption in Southwestern Native Americans, Finnish, Scottish, and Sidney populations <ref>{{cite journal | vauthors = Tabakoff B, Saba L, Printz M, Flodman P, Hodgkinson C, Goldman D, Koob G, Richardson HN, Kechris K, Bell RL, Hübner N, Heinig M, Pravenec M, Mangion J, Legault L, Dongier M, Conigrave KM, Whitfield JB, Saunders J, Grant B, Hoffman PL | display-authors = 6 | title = Genetical genomic determinants of alcohol consumption in rats and humans | journal = BMC Biology | volume = 7 | issue = 1 | pages = 70 | date = October 2009 | pmid = 19874574 | doi = 10.1186/1741-7007-7-70 }}</ref> <ref>{{cite journal | vauthors = Loh EW, Smith I, Murray R, McLaughlin M, McNulty S, Ball D | title = Association between variants at the GABAAbeta2, GABAAalpha6 and GABAAgamma2 gene cluster and alcohol dependence in a Scottish population | journal = Molecular Psychiatry | volume = 4 | issue = 6 | pages = 539–44 | date = November 1999 | pmid = 10578235 | doi = 10.1038/sj.mp.4000554 }}</ref> <ref>{{cite journal | vauthors = Radel M, Vallejo RL, Iwata N, Aragon R, Long JC, Virkkunen M, Goldman D | title = Haplotype-based localization of an alcohol dependence gene to the 5q34 {gamma}-aminobutyric acid type A gene cluster | journal = Archives of General Psychiatry | volume = 62 | issue = 1 | pages = 47–55 | date = January 2005 | pmid = 15630072 | doi = 10.1001/archpsyc.62.1.47 }}</ref>. Chronic alcohol administration induced an increase in the expression of Gabrb2 in a rat model <ref>{{cite journal | vauthors = Devaud LL, Fritschy JM, Sieghart W, Morrow AL | title = Bidirectional alterations of GABA(A) receptor subunit peptide levels in rat cortex during chronic ethanol consumption and withdrawal | journal = Journal of Neurochemistry | volume = 69 | issue = 1 | pages = 126–30 | date = July 1997 | pmid = 9202302 | doi = 10.1046/j.1471-4159.1997.69010126.x }}</ref>. and sleep time was decreased in Gabrb2 knockout mice <ref>{{cite journal | vauthors = Blednov YA, Jung S, Alva H, Wallace D, Rosahl T, Whiting PJ, Harris RA | title = Deletion of the alpha1 or beta2 subunit of GABAA receptors reduces actions of alcohol and other drugs | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 304 | issue = 1 | pages = 30–6 | date = January 2003 | pmid = 12490572 | doi = 10.1124/jpet.102.042960 }}</ref>. |
||
SNPs in GABRB2 were significantly associated with heroin addiction in African American subjects <ref>{{cite journal | |
SNPs in GABRB2 were significantly associated with heroin addiction in African American subjects <ref>{{cite journal | vauthors = Levran O, Peles E, Randesi M, Correa da Rosa J, Ott J, Rotrosen J, Adelson M, Kreek MJ | display-authors = 6 | title = Glutamatergic and GABAergic susceptibility loci for heroin and cocaine addiction in subjects of African and European ancestry | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 64 | pages = 118–23 | date = January 2016 | pmid = 26277529 | doi = 10.1016/j.pnpbp.2015.08.003 }}</ref>. Haplotypes in GABRB2 yielded a significant association with heroin dependence in the Chinese population <ref>{{cite journal | vauthors = Kim YS, Yang M, Mat WK, Tsang SY, Su Z, Jiang X, Ng SK, Liu S, Hu T, Pun F, Liao Y, Tang J, Chen X, Hao W, Xue H | display-authors = 6 | title = GABRB2 Haplotype Association with Heroin Dependence in Chinese Population | journal = PloS One | volume = 10 | issue = 11 | pages = e0142049 | date = 12 November 2015 | pmid = 26561861 | doi = 10.1371/journal.pone.0142049 }}</ref>. |
||
=== Neurological disorders === |
=== Neurological disorders === |
||
==== Epilepsy ==== |
==== Epilepsy ==== |
||
Numerous de novo mutations in GABRB2 were associated with infantile and early childhood epileptic encephalopathy (IECEE) <ref>{{cite journal | |
Numerous de novo mutations in GABRB2 were associated with infantile and early childhood epileptic encephalopathy (IECEE) <ref>{{cite journal | vauthors = Hamdan FF, Myers CT, Cossette P, Lemay P, Spiegelman D, Laporte AD, Nassif C, Diallo O, Monlong J, Cadieux-Dion M, Dobrzeniecka S, Meloche C, Retterer K, Cho MT, Rosenfeld JA, Bi W, Massicotte C, Miguet M, Brunga L, Regan BM, Mo K, Tam C, Schneider A, Hollingsworth G, FitzPatrick DR, Donaldson A, Canham N, Blair E, Kerr B, Fry AE, Thomas RH, Shelagh J, Hurst JA, Brittain H, Blyth M, Lebel RR, Gerkes EH, Davis-Keppen L, Stein Q, Chung WK, Dorison SJ, Benke PJ, Fassi E, Corsten-Janssen N, Kamsteeg EJ, Mau-Them FT, Bruel AL, Verloes A, Õunap K, Wojcik MH, Albert DV, Venkateswaran S, Ware T, Jones D, Liu YC, Mohammad SS, Bizargity P, Bacino CA, Leuzzi V, Martinelli S, Dallapiccola B, Tartaglia M, Blumkin L, Wierenga KJ, Purcarin G, O'Byrne JJ, Stockler S, Lehman A, Keren B, Nougues MC, Mignot C, Auvin S, Nava C, Hiatt SM, Bebin M, Shao Y, Scaglia F, Lalani SR, Frye RE, Jarjour IT, Jacques S, Boucher RM, Riou E, Srour M, Carmant L, Lortie A, Major P, Diadori P, Dubeau F, D'Anjou G, Bourque G, Berkovic SF, Sadleir LG, Campeau PM, Kibar Z, Lafrenière RG, Girard SL, Mercimek-Mahmutoglu S, Boelman C, Rouleau GA, Scheffer IE, Mefford HC, Andrade DM, Rossignol E, Minassian BA, Michaud JL | display-authors = 6 | title = High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies | journal = American Journal of Human Genetics | volume = 101 | issue = 5 | pages = 664–685 | date = November 2017 | pmid = 29100083 | doi = 10.1016/j.ajhg.2017.09.008 }}</ref> <ref>{{cite journal | vauthors = Ishii A, Kang JQ, Schornak CC, Hernandez CC, Shen W, Watkins JC, Macdonald RL, Hirose S | display-authors = 6 | title = A <i>de novo</i> missense mutation of <i>GABRB2</i> causes early myoclonic encephalopathy | journal = Journal of Medical Genetics | volume = 54 | issue = 3 | pages = 202–211 | date = March 2017 | pmid = 27789573 | doi = 10.1136/jmedgenet-2016-104083 }}</ref> <ref>{{cite journal | vauthors = May P, Girard S, Harrer M, Bobbili DR, Schubert J, Wolking S, Becker F, Lachance-Touchette P, Meloche C, Gravel M, Niturad CE, Knaus J, De Kovel C, Toliat M, Polvi A, Iacomino M, Guerrero-López R, Baulac S, Marini C, Thiele H, Altmüller J, Jabbari K, Ruppert AK, Jurkowski W, Lal D, Rusconi R, Cestèle S, Terragni B, Coombs ID, Reid CA, Striano P, Caglayan H, Siren A, Everett K, Møller RS, Hjalgrim H, Muhle H, Helbig I, Kunz WS, Weber YG, Weckhuysen S, Jonghe P, Sisodiya SM, Nabbout R, Franceschetti S, Coppola A, Vari MS, Kasteleijn-Nolst Trenité D, Baykan B, Ozbek U, Bebek N, Klein KM, Rosenow F, Nguyen DK, Dubeau F, Carmant L, Lortie A, Desbiens R, Clément JF, Cieuta-Walti C, Sills GJ, Auce P, Francis B, Johnson MR, Marson AG, Berghuis B, Sander JW, Avbersek A, McCormack M, Cavalleri GL, Delanty N, Depondt C, Krenn M, Zimprich F, Peter S, Nikanorova M, Kraaij R, van Rooij J, Balling R, Ikram MA, Uitterlinden AG, Avanzini G, Schorge S, Petrou S, Mantegazza M, Sander T, LeGuern E, Serratosa JM, Koeleman BP, Palotie A, Lehesjoki AE, Nothnagel M, Nürnberg P, Maljevic S, Zara F, Cossette P, Krause R, Lerche H | display-authors = 6 | title = Rare coding variants in genes encoding GABA<sub>A</sub> receptors in genetic generalised epilepsies: an exome-based case-control study | journal = The Lancet. Neurology | volume = 17 | issue = 8 | pages = 699–708 | date = August 2018 | pmid = 30033060 | doi = 10.1016/S1474-4422(18)30215-1 }}</ref> <ref>{{cite journal | vauthors = Bosch DG, Boonstra FN, de Leeuw N, Pfundt R, Nillesen WM, de Ligt J, Gilissen C, Jhangiani S, Lupski JR, Cremers FP, de Vries BB | display-authors = 6 | title = Novel genetic causes for cerebral visual impairment | journal = European Journal of Human Genetics | volume = 24 | issue = 5 | pages = 660–5 | date = May 2016 | pmid = 26350515 | doi = 10.1038/ejhg.2015.186 }}</ref> <ref>{{cite journal | vauthors = Srivastava S, Cohen J, Pevsner J, Aradhya S, McKnight D, Butler E, Johnston M, Fatemi A | display-authors = 6 | title = A novel variant in GABRB2 associated with intellectual disability and epilepsy | journal = American Journal of Medical Genetics. Part A | volume = 164A | issue = 11 | pages = 2914–21 | date = November 2014 | pmid = 25124326 | doi = 10.1002/ajmg.a.36714 }}</ref>. As well, SNPs in GABRB2 were significantly associated with epilepsy in the North Indian population <ref>{{cite journal | vauthors = Kumari R, Lakhan R, Kalita J, Garg RK, Misra UK, Mittal B | title = Potential role of GABAA receptor subunit; GABRA6, GABRB2 and GABRR2 gene polymorphisms in epilepsy susceptibility and pharmacotherapy in North Indian population | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 412 | issue = 13-14 | pages = 1244–8 | date = June 2011 | pmid = 21420396 | doi = 10.1016/j.cca.2011.03.018 }}</ref>. Moreover, Gabrb2 knockout mice displayed audiogenic epilepsy, which further confirmed the contribution of GABRB2 to the etiology of epilepsy <ref>{{cite journal | vauthors = Yeung RK, Xiang ZH, Tsang SY, Li R, Ho TY, Li Q, Hui CK, Sham PC, Qiao MQ, Xue H | display-authors = 6 | title = Gabrb2-knockout mice displayed schizophrenia-like and comorbid phenotypes with interneuron-astrocyte-microglia dysregulation | journal = Translational Psychiatry | volume = 8 | issue = 1 | pages = 128 | date = July 2018 | pmid = 30013074 | doi = 10.1038/s41398-018-0176-9 }}</ref>. |
||
==== Autism spectrum disorder ==== |
==== Autism spectrum disorder ==== |
||
The density of GABAA receptors showed a significant reduction in autistic brains |
The density of GABAA receptors showed a significant reduction in autistic brains.<ref>{{cite journal | vauthors = Blatt GJ, Fitzgerald CM, Guptill JT, Booker AB, Kemper TL, Bauman ML | title = Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study | journal = Journal of Autism and Developmental Disorders | volume = 31 | issue = 6 | pages = 537–43 | date = December 2001 | pmid = 11814263 | doi = 10.1023/a:1013238809666 }}</ref> and SNPs in GABRB2 were significantly associated with autism <ref>{{cite journal | vauthors = Ma DQ, Whitehead PL, Menold MM, Martin ER, Ashley-Koch AE, Mei H, Ritchie MD, Delong GR, Abramson RK, Wright HH, Cuccaro ML, Hussman JP, Gilbert JR, Pericak-Vance MA | display-authors = 6 | title = Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism | journal = American Journal of Human Genetics | volume = 77 | issue = 3 | pages = 377–88 | date = September 2005 | pmid = 16080114 | doi = 10.1086/433195 }}</ref>. De novo pathogenic mutations in the GABRB2 gene contribute to the physiopathology of Rett syndrome <ref>{{cite journal | vauthors = Cogliati F, Giorgini V, Masciadri M, Bonati MT, Marchi M, Cracco I, Gentilini D, Peron A, Savini MN, Spaccini L, Scelsa B, Maitz S, Veneselli E, Prato G, Pintaudi M, Moroni I, Vignoli A, Larizza L, Russo S | display-authors = 6 | title = Pathogenic Variants in <i>STXBP1</i> and in Genes for GABAa Receptor Subunities Cause Atypical Rett/Rett-like Phenotypes | journal = International Journal of Molecular Sciences | volume = 20 | issue = 15 | pages = 3621 | date = July 2019 | pmid = 31344879 | doi = 10.3390/ijms20153621 }}</ref> <ref>{{cite journal | vauthors = Sajan SA, Jhangiani SN, Muzny DM, Gibbs RA, Lupski JR, Glaze DG, Kaufmann WE, Skinner SA, Annese F, Friez MJ, Lane J, Percy AK, Neul JL | display-authors = 6 | title = Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2 | journal = Genetics in Medicine | volume = 19 | issue = 1 | pages = 13–19 | date = January 2017 | pmid = 27171548 | doi = 10.1038/gim.2016.42 }}</ref>. β2 subunit mRNA expression level was subjected to significant upregulation in a mouse model of Rett syndrome <ref>{{cite journal | vauthors = Chen CY, Di Lucente J, Lin YC, Lien CC, Rogawski MA, Maezawa I, Jin LW | title = Defective GABAergic neurotransmission in the nucleus tractus solitarius in Mecp2-null mice, a model of Rett syndrome | journal = Neurobiology of Disease | volume = 109 | issue = Pt A | pages = 25–32 | date = January 2018 | pmid = 28927958 | doi = 10.1016/j.nbd.2017.09.006 }}</ref> |
||
=== Neurodegenerative disorders === |
=== Neurodegenerative disorders === |
||
Deficits in the GABergic system and decreased levels of GABA were reported in Alzheimer's disease (AD) <ref>{{cite journal | |
Deficits in the GABergic system and decreased levels of GABA were reported in Alzheimer's disease (AD) <ref>{{cite journal | vauthors = Li Y, Sun H, Chen Z, Xu H, Bu G, Zheng H | title = Implications of GABAergic Neurotransmission in Alzheimer's Disease | journal = Frontiers in Aging Neuroscience | volume = 8 | pages = 31 | date = 23 February 2016 | pmid = 26941642 | doi = 10.3389/fnagi.2016.00031 }}</ref>. An SNP near GABRB2 was associated with AD <ref>{{cite journal | vauthors = Li JQ, Yuan XZ, Li HY, Cao XP, Yu JT, Tan L, Chen WA | title = Genome-wide association study identifies two loci influencing plasma neurofilament light levels | journal = BMC Medical Genomics | volume = 11 | issue = 1 | pages = 47 | date = May 2018 | pmid = 29747637 | doi = 10.1186/s12920-018-0364-8 }}</ref>. Two SNPs in GABRB2 were significantly associated with frontotemporal dementia (FTD) risk, and GABRB2 was downregulated in a cellular system of FTD and a mouse model of tauopathy <ref>{{cite journal | vauthors = Jiang S, Wen N, Li Z, Dube U, Del Aguila J, Budde J, Martinez R, Hsu S, Fernandez MV, Cairns NJ, Harari O, Cruchaga C, Karch CM | display-authors = 6 | title = Integrative system biology analyses of CRISPR-edited iPSC-derived neurons and human brains reveal deficiencies of presynaptic signaling in FTLD and PSP | journal = Translational Psychiatry | volume = 8 | issue = 1 | pages = 265 | date = December 2018 | pmid = 30546007 | doi = 10.1038/s41398-018-0319-z }}</ref> <ref>{{cite journal | vauthors = Matarin M, Salih DA, Yasvoina M, Cummings DM, Guelfi S, Liu W, Nahaboo Solim MA, Moens TG, Paublete RM, Ali SS, Perona M, Desai R, Smith KJ, Latcham J, Fulleylove M, Richardson JC, Hardy J, Edwards FA | display-authors = 6 | title = A genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology | journal = Cell Reports | volume = 10 | issue = 4 | pages = 633–44 | date = February 2015 | pmid = 25620700 | doi = 10.1016/j.celrep.2014.12.041 }}</ref>. |
||
=== Cancer === |
=== Cancer === |
||
Genomic classifiers including GABRB2 could differentiate correctly between malignant and benign nodules <ref>{{cite journal | |
Genomic classifiers including GABRB2 could differentiate correctly between malignant and benign nodules <ref>{{cite journal | vauthors = Wiseman SM, Haddad Z, Walker B, Vergara IA, Sierocinski T, Crisan A, Ghadessi M, Dao P, Zimmermann B, Triche TJ, Erho N, Davicioni E | display-authors = 6 | title = Whole-transcriptome profiling of thyroid nodules identifies expression-based signatures for accurate thyroid cancer diagnosis | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 98 | issue = 10 | pages = 4072–9 | date = October 2013 | pmid = 23928671 | doi = 10.1210/jc.2013-1991 }}</ref> <ref>{{cite journal | vauthors = Alexander EK, Kennedy GC, Baloch ZW, Cibas ES, Chudova D, Diggans J, Friedman L, Kloos RT, LiVolsi VA, Mandel SJ, Raab SS, Rosai J, Steward DL, Walsh PS, Wilde JI, Zeiger MA, Lanman RB, Haugen BR | display-authors = 6 | title = Preoperative diagnosis of benign thyroid nodules with indeterminate cytology | journal = The New England Journal of Medicine | volume = 367 | issue = 8 | pages = 705–15 | date = August 2012 | pmid = 22731672 | doi = 10.1056/NEJMoa1203208 }}</ref>. and GABRB2 alone or in combination with other genes correctly distinguished between malignant and benign tumors <ref>{{cite journal | vauthors = Barros-Filho MC, Marchi FA, Pinto CA, Rogatto SR, Kowalski LP | title = High Diagnostic Accuracy Based on CLDN10, HMGA2, and LAMB3 Transcripts in Papillary Thyroid Carcinoma | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 100 | issue = 6 | pages = E890-9 | date = June 2015 | pmid = 25867809 | doi = 10.1210/jc.2014-4053 }}</ref> <ref>{{cite journal | vauthors = Wang QX, Chen ED, Cai YF, Li Q, Jin YX, Jin WX, Wang YH, Zheng ZC, Xue L, Wang OC, Zhang XH | display-authors = 6 | title = A panel of four genes accurately differentiates benign from malignant thyroid nodules | journal = Journal of Experimental & Clinical Cancer Research | volume = 35 | issue = 1 | pages = 169 | date = October 2016 | pmid = 27793213 | doi = 10.1186/s13046-016-0447-3 }}</ref>. GABRB2 was upregulated and hypomethylated in papillary thyroid carcinoma. The downregulation of GABRB2 enhanced the apoptotic cell death and decreased proliferation, migration, and invasiveness of thyroid cancer cells <ref>{{cite journal | vauthors = Beltrami CM, Dos Reis MB, Barros-Filho MC, Marchi FA, Kuasne H, Pinto CA, Ambatipudi S, Herceg Z, Kowalski LP, Rogatto SR | display-authors = 6 | title = Integrated data analysis reveals potential drivers and pathways disrupted by DNA methylation in papillary thyroid carcinomas | journal = Clinical Epigenetics | volume = 9 | issue = 1 | pages = 45 | date = December 2017 | pmid = 28469731 | doi = 10.1186/s13148-017-0346-2 }}</ref> <ref>{{cite journal | vauthors = Jin Y, Jin W, Zheng Z, Chen E, Wang Q, Wang Y, Wang O, Zhang X | display-authors = 6 | title = GABRB2 plays an important role in the lymph node metastasis of papillary thyroid cancer | journal = Biochemical and Biophysical Research Communications | volume = 492 | issue = 3 | pages = 323–330 | date = October 2017 | pmid = 28859983 | doi = 10.1016/j.bbrc.2017.08.114 }}</ref>. |
||
GABRB2 was upregulated in adrenocortical carcinoma and salivary gland cancer <ref>{{cite journal | |
GABRB2 was upregulated in adrenocortical carcinoma and salivary gland cancer <ref>{{cite journal | vauthors = Knott EL, Leidenheimer NJ | title = A Targeted Bioinformatics Assessment of Adrenocortical Carcinoma Reveals Prognostic Implications of GABA System Gene Expression | journal = International Journal of Molecular Sciences | volume = 21 | issue = 22 | date = November 2020 | pmid = 33187258 | doi = 10.3390/ijms21228485 }}</ref> <ref>{{cite journal | vauthors = Chen W, Liu BY, Zhang X, Zhao XG, Cao G, Dong Z, Zhang SL | title = Identification of differentially expressed genes in salivary adenoid cystic carcinoma cells associated with metastasis | journal = Archives of Medical Science | volume = 12 | issue = 4 | pages = 881–8 | date = August 2016 | pmid = 27478471 | doi = 10.5114/aoms.2016.60973 }}</ref>. but downregulated in patients with colorectal cancer, brain tumors, kidney renal clear cell carcinoma and lung cancer <ref>{{cite journal | vauthors = Gross AM, Kreisberg JF, Ideker T | title = Analysis of Matched Tumor and Normal Profiles Reveals Common Transcriptional and Epigenetic Signals Shared across Cancer Types | journal = PloS One | volume = 10 | issue = 11 | pages = e0142618 | date = 10 November 2015 | pmid = 26555223 | doi = 10.1371/journal.pone.0142618 }}</ref> <ref>{{cite journal | vauthors = Liu A, Zhao H, Sun B, Han X, Zhou D, Cui Z, Ma X, Zhang J, Yuan L | display-authors = 6 | title = A predictive analysis approach for paediatric and adult high-grade glioma: miRNAs and network insight | journal = Annals of Translational Medicine | volume = 8 | issue = 5 | pages = 242 | date = March 2020 | pmid = 32309389 | doi = 10.21037/atm.2020.01.12 }}</ref> <ref>{{cite journal | vauthors = Liu BX, Huang GJ, Cheng HB | title = Comprehensive Analysis of Core Genes and Potential Mechanisms in Rectal Cancer | journal = Journal of Computational Biology | volume = 26 | issue = 11 | pages = 1262–1277 | date = November 2019 | pmid = 31211595 | doi = 10.1089/cmb.2019.0073 }}</ref> <ref>{{cite journal | vauthors = Markert JM, Fuller CM, Gillespie GY, Bubien JK, McLean LA, Hong RL, Lee K, Gullans SR, Mapstone TB, Benos DJ | display-authors = 6 | title = Differential gene expression profiling in human brain tumors | journal = Physiological Genomics | volume = 5 | issue = 1 | pages = 21–33 | date = February 2001 | pmid = 11161003 | doi = 10.1152/physiolgenomics.2001.5.1.21 }}</ref> <ref>{{cite journal | vauthors = Narasimhan K, Gauthaman K, Pushparaj PN, Meenakumari G, Chaudhary AG, Abuzenadah A, Gari MA, Al Qahtani M, Manikandan J | display-authors = 6 |title=Identification of Unique miRNA Biomarkers in Colorectal Adenoma and Carcinoma Using Microarray: Evaluation of Their Putative Role in Disease Progression |journal=ISRN Cell Biology |date=22 April 2014 |volume=2014 |pages=1–10 |doi=10.1155/2014/526075}}</ref> <ref>{{cite journal | vauthors = Yan L, Gong YZ, Shao MN, Ruan GT, Xie HL, Liao XW, Wang XK, Han QF, Zhou X, Zhu LC, Gao F, Gan JL | display-authors = 6 | title = Distinct diagnostic and prognostic values of γ-aminobutyric acid type A receptor family genes in patients with colon adenocarcinoma | journal = Oncology Letters | volume = 20 | issue = 1 | pages = 275–291 | date = July 2020 | pmid = 32565954 | doi = 10.3892/ol.2020.11573 }}</ref> |
||
== Therapeutic implications == |
== Therapeutic implications == |
||
The β2 subunit-containing GABAA receptors are more sensitive to GABA <ref>{{cite journal | |
The β2 subunit-containing GABAA receptors are more sensitive to GABA <ref>{{cite journal | vauthors = Hartiadi LY, Ahring PK, Chebib M, Absalom NL | title = High and low GABA sensitivity α4β2δ GABAA receptors are expressed in Xenopus laevis oocytes with divergent stoichiometries | journal = Biochemical Pharmacology | volume = 103 | pages = 98–108 | date = March 2016 | pmid = 26774457 | doi = 10.1016/j.bcp.2015.12.021 }}</ref>. Tyrosine and proline residues in the Cys-loop of this subunit were important elements in the binding and response to GABA <ref>{{cite journal | vauthors = Laha KT, Tran PN | title = Multiple tyrosine residues at the GABA binding pocket influence surface expression and mediate kinetics of the GABAA receptor | journal = Journal of Neurochemistry | volume = 124 | issue = 2 | pages = 200–9 | date = January 2013 | pmid = 23121119 | doi = 10.1111/jnc.12083 }}</ref> <ref>{{cite journal | vauthors = Tierney ML, Luu T, Gage PW | title = Functional asymmetry of the conserved cystine loops in alphabetagamma GABA A receptors revealed by the response to GABA activation and drug potentiation | journal = The International Journal of Biochemistry & Cell Biology | volume = 40 | issue = 5 | pages = 968–79 | date = January 2008 | pmid = 18083058 | doi = 10.1016/j.biocel.2007.10.029 }}</ref>, and the subunit also mediated the receptor binding of alcohol and anesthetics, anticonvulsive activity of loreclezole, hypothermic response to etomidate, as well as the sedative effects of both etomidate and loreclezole <ref>{{cite journal | vauthors = McCracken ML, Borghese CM, Trudell JR, Harris RA | title = A transmembrane amino acid in the GABAA receptor β2 subunit critical for the actions of alcohols and anesthetics | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 335 | issue = 3 | pages = 600–6 | date = December 2010 | pmid = 20826568 | doi = 10.1124/jpet.110.170472 }}</ref> <ref>{{cite journal | vauthors = Cirone J, Rosahl TW, Reynolds DS, Newman RJ, O'Meara GF, Hutson PH, Wafford KA | title = Gamma-aminobutyric acid type A receptor beta 2 subunit mediates the hypothermic effect of etomidate in mice | journal = Anesthesiology | volume = 100 | issue = 6 | pages = 1438–45 | date = June 2004 | pmid = 15166563 | doi = 10.1097/00000542-200406000-00016 }}</ref> <ref>{{cite journal | vauthors = Groves JO, Guscott MR, Hallett DJ, Rosahl TW, Pike A, Davies A, Wafford KA, Reynolds DS | display-authors = 6 | title = The role of GABAbeta2 subunit-containing receptors in mediating the anticonvulsant and sedative effects of loreclezole | journal = The European Journal of Neuroscience | volume = 24 | issue = 1 | pages = 167–74 | date = July 2006 | pmid = 16882014 | doi = 10.1111/j.1460-9568.2006.04890.x }}</ref>. It was identified as a target for the endocannabinoid 2-arachidonylglycerol <ref>{{cite journal | vauthors = Baur R, Kielar M, Richter L, Ernst M, Ecker GF, Sigel E | title = Molecular analysis of the site for 2-arachidonylglycerol (2-AG) on the β₂ subunit of GABA(A) receptors | journal = Journal of Neurochemistry | volume = 126 | issue = 1 | pages = 29–36 | date = July 2013 | pmid = 23600744 | doi = 10.1111/jnc.12270 }}</ref>, and Gabrb2 expression was upregulated by the antiepileptic drug qingyangshenylycosides and downregulated by the opioid oxycodone <ref>{{cite journal | vauthors = Li X, Yang Q, Hu Y | title = Regulation of the expression of GABAA receptor subunits by an antiepileptic drug QYS | journal = Neuroscience Letters | volume = 392 | issue = 1-2 | pages = 145–9 | date = January 2006 | pmid = 16214289 | doi = 10.1016/j.neulet.2005.09.011 }}</ref> <ref>{{cite journal | vauthors = Zhang Y, Mayer-Blackwell B, Schlussman SD, Randesi M, Butelman ER, Ho A, Ott J, Kreek MJ | display-authors = 6 | title = Extended access oxycodone self-administration and neurotransmitter receptor gene expression in the dorsal striatum of adult C57BL/6 J mice | journal = Psychopharmacology | volume = 231 | issue = 7 | pages = 1277–87 | date = April 2014 | pmid = 24221825 | doi = 10.1007/s00213-013-3306-3 }}</ref>. The wide-ranging involvement of the GABRB2 and its gene products in neuropsychiatric pharmacology are in accord with their central roles in inhibitory signaling in the brain. |
||
== See also == |
== See also == |
||
Revision as of 08:26, 16 March 2021
The GABAA beta-2 subunit is a protein that in humans is encoded by the GABRB2 gene. It combines with other subunits to form the ionotropic GABAA receptors. GABA (γ-aminobutyric acid) system is the major inhibitory system in the brain, and its dominant GABAA receptor subtype is composed of α1, β2, and γ2 subunits with the stoichiometry of 2:2:1, which accounts for 43% of all GABAA receptors[5][6] Alternative splicing of the GABRB2 gene leads at least to four isoforms, viz. β2-long (β2L) and β2-short (β2S, β2S1, and β2S2). Alternatively spliced variants displayed similar but non-identical electrophysiological properties[7]. GABRB2 is subjected to positive selection and known to be both an alternative splicing and a recombination hotspot; it is regulated via epigenetic regulation including imprinting and gene and promoter methylation [8] [9][10] GABRB2 has been associated with a number of neuropsychiatric disorders, and found to display altered expression in cancer.
Structure
GABRB2 encodes the GABAA receptor beta-2 subunit. It is highly expressed in the brain with dominance in the gray matter [11]. In humans, it is located on chromosome 5q34, with 11 exons and 10 introns spanning more than 260 kb, and a promoter region ranging from 1000 bp upstream to 689 bp downstream of exon 1 [12]. Alternative splicing of the gene product yields at least four isoforms, viz. β2-long (β2L), β2-short (β2S) and two additional short isoforms β2S1 and β2S2. These isoforms, composed of 512, 474, 313, and 372 amino acids respectively [13], display dissimilar electrophysiological properties [14]. In mice, the corresponding Gabrb2 gene on chromosome 11A5 comprises 12 exons and 11 introns, and the two isoforms β2L and β2S from alternative splicing consisted of 512 and 474 amino acids respectively [15]. The β-2 subunit is a component of the ligand-gated chloride GABAA receptors which belongs to the Cys-loop superfamily [16]. Like all subunits of this family, it consists of an extracellular N-terminal domain containing a Cys-loop of 13 amino acids, four membrane-spanning domains (TM1-4) with a large intracellular loop between TM3 and TM4, and an extracellular C-terminal domain [17]. Five subunits from varied families (α1-6, β1-3, γ1-3, δ, ε, π, θ, ρ1-3) combine to form the heteropentameric GABAA receptor. TM2 from each subunit participates in the formation of the ion pore of the receptor, and α2β2γ2 is the major subtype in the brain that accounts for 43% of all GABAA receptors [18] [19].
Regulation
Phosphorylation is an important mechanism for the modulation of GABAA receptor function [20].GABRB2 includes a consensus sequence for a calmodulin-dependent protein kinase II within exon 10 which is only expressed by β2L. As a result, upon repetitive stimulation, the β2L isoform-containing GABAA receptors are more vulnerable to run-down than those containing the short isoforms. Accordingly, ATP depletion reduces the inhibitory transmission of the GABAergic system due to GABAA receptors rundown through β2. Since this rundown occasioned by the presence of β2L would lead to improved maintenance of survival-favoring activities such as hunting and food gathering in the face of energy deprivation, it could be selected as an evolutionary advantage over the shorter isoforms [21] [22] [23]. Multiple lines of evidence confirmed the epigenetic regulation of GABRB2 gene expression via methylation and imprinting. GABRB2 mRNA expression level varied with germline genotypes, and with the gender of the parent in accord with the process of imprinting [24] [25] [26] [27].
Function
GABRB2 is highly expressed in the brain where it plays its major role [28]. In the immature brain, GABAA receptors participate in excitatory transmission [29], which is important to synaptogenesis, neurogenesis, and the formation of the glutamatergic system [30]. In the mature brain, GABAA receptors fulfill their conventional inhibitory role, with the β2 subunits participating in some of the fastest inhibitory transmissions that prevent hyperexcitability, regulate the stress response of the hypothalamic-pituitary-adrenal axis, as well as pain signals mediated by the thalamus [31] [32]. Moreover, GABRB2 is associated with cognitive function, energy regulation, time perception [33], and the maintenance of efferent synaptic terminals in the mature ear [34].
Clinical significance
GABRB2 is associated with a spectrum of neuropsychiatric disorders, and displays of differential gene expression between tumor and non tumor tissues.
Psychiatric disorders
Schizophrenia
Single nucleotide polymorphisms (SNPs) in GABRB2 were first associated with schizophrenia (SCZ) in Han Chinese, and confirmed subsequently for German, Portuguese, and Japanese SCZ patients [35] [36] [37] [38] [39]. Furthermore, their significant associations have been extended to cognitive function, psychosis, and neuroleptic-induced tardive dyskinesia in schizophrenics [40] [41] [42]. Recurrent copy number variations (CNVs) in GABRB2 were likewise associated with schizophrenia [43]. GABRB2 expression was decreased in genotype and age-dependent manners, with reduced β2L/β2S ratios in schizophrenics serving as a key determinant of the response of receptor function to the energy status [44] [45]. The regulation of its expression by methylation and imprinting [46] [47] [48], as well as its N-glycosylation of the β2-subunit, were altered in SCZ [49]. That GABRB2 is both a recombination hotspot and subject to positive selection could be an important factor in the widespread occurrence of SCZ [50]. Gabrb2-knockout mice displayed schizophrenia-like behavior including prepulse inhibition deficit and antisocial behavior that were ameliorated by the antipsychotic risperidone, strongly supporting the proposal based on postmortem SCZ brains that GABRB2 represents the key genetic factor in SCZ etiology [51].
Other psychiatric disorders
GABRB2 was significantly associated with bipolar disorder, with a genotype-dependent decrease in GABRB2 mRNA levels weaker than that observed in SCZ [52] [53] [54] [55]. In major depressive disorder, the expressions of GABAA subunit genes were altered [56], and the expression of GABRB2 was significantly decreased in the anterior cingulate cortex, in the postmortem brains of patients [57]. The expression of GABRB2 was significantly increased in the internet gaming disorder group, and GABRB2 was the downstream target for two circulating microRNA, viz. hsa-miR-26b-5p and hsa-miR-652-3p, which were significantly downregulated in these subjects [58]. The GABAergic system was suggested to be a factor in the physiopathology of premenstrual dysphoric disorder (PMDD) [59]. GABA levels were altered in the brain of PMDD patients [60]. Two highly recurrent copy number variations in GABRB2 were associated with PMDD in Chinese and German patients, providing thereby a possible explanation of part of the complex psychological symptoms of PMDD [61].
Drug dependence
SNPs in GABRB2 were significantly associated with alcohol dependence and consumption in Southwestern Native Americans, Finnish, Scottish, and Sidney populations [62] [63] [64]. Chronic alcohol administration induced an increase in the expression of Gabrb2 in a rat model [65]. and sleep time was decreased in Gabrb2 knockout mice [66]. SNPs in GABRB2 were significantly associated with heroin addiction in African American subjects [67]. Haplotypes in GABRB2 yielded a significant association with heroin dependence in the Chinese population [68].
Neurological disorders
Epilepsy
Numerous de novo mutations in GABRB2 were associated with infantile and early childhood epileptic encephalopathy (IECEE) [69] [70] [71] [72] [73]. As well, SNPs in GABRB2 were significantly associated with epilepsy in the North Indian population [74]. Moreover, Gabrb2 knockout mice displayed audiogenic epilepsy, which further confirmed the contribution of GABRB2 to the etiology of epilepsy [75].
Autism spectrum disorder
The density of GABAA receptors showed a significant reduction in autistic brains.[76] and SNPs in GABRB2 were significantly associated with autism [77]. De novo pathogenic mutations in the GABRB2 gene contribute to the physiopathology of Rett syndrome [78] [79]. β2 subunit mRNA expression level was subjected to significant upregulation in a mouse model of Rett syndrome [80]
Neurodegenerative disorders
Deficits in the GABergic system and decreased levels of GABA were reported in Alzheimer's disease (AD) [81]. An SNP near GABRB2 was associated with AD [82]. Two SNPs in GABRB2 were significantly associated with frontotemporal dementia (FTD) risk, and GABRB2 was downregulated in a cellular system of FTD and a mouse model of tauopathy [83] [84].
Cancer
Genomic classifiers including GABRB2 could differentiate correctly between malignant and benign nodules [85] [86]. and GABRB2 alone or in combination with other genes correctly distinguished between malignant and benign tumors [87] [88]. GABRB2 was upregulated and hypomethylated in papillary thyroid carcinoma. The downregulation of GABRB2 enhanced the apoptotic cell death and decreased proliferation, migration, and invasiveness of thyroid cancer cells [89] [90]. GABRB2 was upregulated in adrenocortical carcinoma and salivary gland cancer [91] [92]. but downregulated in patients with colorectal cancer, brain tumors, kidney renal clear cell carcinoma and lung cancer [93] [94] [95] [96] [97] [98]
Therapeutic implications
The β2 subunit-containing GABAA receptors are more sensitive to GABA [99]. Tyrosine and proline residues in the Cys-loop of this subunit were important elements in the binding and response to GABA [100] [101], and the subunit also mediated the receptor binding of alcohol and anesthetics, anticonvulsive activity of loreclezole, hypothermic response to etomidate, as well as the sedative effects of both etomidate and loreclezole [102] [103] [104]. It was identified as a target for the endocannabinoid 2-arachidonylglycerol [105], and Gabrb2 expression was upregulated by the antiepileptic drug qingyangshenylycosides and downregulated by the opioid oxycodone [106] [107]. The wide-ranging involvement of the GABRB2 and its gene products in neuropsychiatric pharmacology are in accord with their central roles in inhibitory signaling in the brain.
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000145864 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000007653 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ McKernan RM, Whiting PJ (April 1996). "Which GABAA-receptor subtypes really occur in the brain?". Trends in Neurosciences. 19 (4): 139–43. doi:10.1016/s0166-2236(96)80023-3. PMID 8658597.
- ^ McCracken ML, Borghese CM, Trudell JR, Harris RA (December 2010). "A transmembrane amino acid in the GABAA receptor β2 subunit critical for the actions of alcohols and anesthetics". The Journal of Pharmacology and Experimental Therapeutics. 335 (3): 600–6. doi:10.1124/jpet.110.170472. PMID 20826568.
- ^ Zhao C, Xu Z, Wang F, Chen J, Ng SK, Wong PW, et al. (September 2009). "Alternative-splicing in the exon-10 region of GABA(A) receptor beta(2) subunit gene: relationships between novel isoforms and psychotic disorders". PloS One. 4 (9): e6977. doi:10.1371/journal.pone.0006977. PMID 19763268.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Lo WS, Xu Z, Yu Z, Pun FW, Ng SK, Chen J, et al. (May 2007). "Positive selection within the Schizophrenia-associated GABA(A) receptor beta(2) gene". PloS One. 2 (5): e462. doi:10.1371/journal.pone.0000462. PMID 17520021.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Pun FW, Zhao C, Lo WS, Ng SK, Tsang SY, Nimgaonkar V, et al. (May 2011). "Imprinting in the schizophrenia candidate gene GABRB2 encoding GABA(A) receptor β(2) subunit". Molecular Psychiatry. 16 (5): 557–68. doi:10.1038/mp.2010.47. PMID 20404824.
- ^ Zhao C, Wang F, Pun FW, Mei L, Ren L, Yu Z, et al. (February 2012). "Epigenetic regulation on GABRB2 isoforms expression: developmental variations and disruptions in psychotic disorders". Schizophrenia Research. 134 (2–3): 260–6. doi:10.1016/j.schres.2011.11.029. PMID 22206711.
- ^ Zhao C, Xu Z, Chen J, Yu Z, Tong KL, Lo WS, et al. (December 2006). "Two isoforms of GABA(A) receptor beta2 subunit with different electrophysiological properties: Differential expression and genotypical correlations in schizophrenia". Molecular Psychiatry. 11 (12): 1092–105. doi:10.1038/sj.mp.4001899. PMID 16983389.
- ^ "GABRB2 gamma-aminobutyric acid type A receptor subunit beta2 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov.
- ^ "GABRB2 - Gamma-aminobutyric acid receptor subunit beta-2 precursor - Homo sapiens (Human) - GABRB2 gene & protein". www.uniprot.org.
- ^ Zhao C, Xu Z, Chen J, Yu Z, Tong KL, Lo WS, et al. (December 2006). "Two isoforms of GABA(A) receptor beta2 subunit with different electrophysiological properties: Differential expression and genotypical correlations in schizophrenia". Molecular Psychiatry. 11 (12): 1092–105. doi:10.1038/sj.mp.4001899. PMID 16983389.
- ^ "Gabrb2 - Gamma-aminobutyric acid receptor subunit beta-2 precursor - Mus musculus (Mouse) - Gabrb2 gene & protein". www.uniprot.org.
- ^ Hirose S (2014). "Mutant GABA(A) receptor subunits in genetic (idiopathic) epilepsy". Progress in Brain Research. 213: 55–85. doi:10.1016/B978-0-444-63326-2.00003-X. PMID 25194483.
- ^ Cheng J, Ju XL, Chen XY, Liu GY (September 2009). "Homology modeling of human alpha 1 beta 2 gamma 2 and house fly beta 3 GABA receptor channels and Surflex-docking of fipronil". Journal of Molecular Modeling. 15 (9): 1145–53. doi:10.1007/s00894-009-0477-2. PMID 19238461.
- ^ Houston CM, Lee HH, Hosie AM, Moss SJ, Smart TG (June 2007). "Identification of the sites for CaMK-II-dependent phosphorylation of GABA(A) receptors". The Journal of Biological Chemistry. 282 (24): 17855–65. doi:10.1074/jbc.M611533200. PMID 17442679.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ McKernan RM, Whiting PJ (April 1996). "Which GABAA-receptor subtypes really occur in the brain?". Trends in Neurosciences. 19 (4): 139–43. doi:10.1016/s0166-2236(96)80023-3. PMID 8658597.
- ^ Baumann SW, Baur R, Sigel E (November 2002). "Forced subunit assembly in alpha1beta2gamma2 GABAA receptors. Insight into the absolute arrangement". The Journal of Biological Chemistry. 277 (48): 46020–5. doi:10.1074/jbc.M207663200. PMID 12324466.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Palma E, Ragozzino DA, Di Angelantonio S, Spinelli G, Trettel F, Martinez-Torres A, et al. (July 2004). "Phosphatase inhibitors remove the run-down of gamma-aminobutyric acid type A receptors in the human epileptic brain". Proceedings of the National Academy of Sciences of the United States of America. 101 (27): 10183–8. doi:10.1073/pnas.0403683101. PMID 15218107.
- ^ Lo WS, Xu Z, Yu Z, Pun FW, Ng SK, Chen J, et al. (May 2007). "Positive selection within the Schizophrenia-associated GABA(A) receptor beta(2) gene". PloS One. 2 (5): e462. doi:10.1371/journal.pone.0000462. PMID 17520021.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Zhao C, Xu Z, Chen J, Yu Z, Tong KL, Lo WS, et al. (December 2006). "Two isoforms of GABA(A) receptor beta2 subunit with different electrophysiological properties: Differential expression and genotypical correlations in schizophrenia". Molecular Psychiatry. 11 (12): 1092–105. doi:10.1038/sj.mp.4001899. PMID 16983389.
- ^ Pun FW, Zhao C, Lo WS, Ng SK, Tsang SY, Nimgaonkar V, et al. (May 2011). "Imprinting in the schizophrenia candidate gene GABRB2 encoding GABA(A) receptor β(2) subunit". Molecular Psychiatry. 16 (5): 557–68. doi:10.1038/mp.2010.47. PMID 20404824.
- ^ Wang L, Jiang W, Lin Q, Zhang Y, Zhao C (November 2016). "DNA methylation regulates gabrb2 mRNA expression: developmental variations and disruptions in l-methionine-induced zebrafish with schizophrenia-like symptoms". Genes, Brain, and Behavior. 15 (8): 702–710. doi:10.1111/gbb.12315. PMID 27509263.
- ^ Zhao C, Wang F, Pun FW, Mei L, Ren L, Yu Z, et al. (February 2012). "Epigenetic regulation on GABRB2 isoforms expression: developmental variations and disruptions in psychotic disorders". Schizophrenia Research. 134 (2–3): 260–6. doi:10.1016/j.schres.2011.11.029. PMID 22206711.
- ^ Zong L, Zhou L, Hou Y, Zhang L, Jiang W, Zhang W, et al. (May 2017). "Genetic and epigenetic regulation on the transcription of GABRB2: Genotype-dependent hydroxymethylation and methylation alterations in schizophrenia". Journal of Psychiatric Research. 88: 9–17. doi:10.1016/j.jpsychires.2016.12.019. PMID 28063323.
- ^ Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, et al. (February 2014). "Analysis of the Human Tissue-specific Expression by Genome-wide Integration of Transcriptomics and Antibody-based Proteomics". Molecular & Cellular Proteomics. 13 (2): 397–406. doi:10.1074/mcp.M113.035600. PMID 33498127.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Ben-Ari Y, Gaiarsa JL, Tyzio R, Khazipov R (October 2007). "GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations". Physiological Reviews. 87 (4): 1215–84. doi:10.1152/physrev.00017.2006. PMID 17928584.
- ^ Chen G, Trombley PQ, van den Pol AN (October 1995). "GABA receptors precede glutamate receptors in hypothalamic development; differential regulation by astrocytes". Journal of Neurophysiology. 74 (4): 1473–84. doi:10.1152/jn.1995.74.4.1473. PMID 8989386.
- ^ Zhang Q, Long Q, Ott J (June 2014). "AprioriGWAS, a new pattern mining strategy for detecting genetic variants associated with disease through interaction effects". PLoS Computational Biology. 10 (6): e1003627. doi:10.1371/journal.pcbi.1003627. PMID 24901472.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Herman JP, Mueller NK, Figueiredo H (June 2004). "Role of GABA and glutamate circuitry in hypothalamo-pituitary-adrenocortical stress integration". Annals of the New York Academy of Sciences. 1018 (1): 35–45. doi:10.1196/annals.1296.004. PMID 15240350.
- ^ Marinho V, Oliveira T, Bandeira J, Pinto GR, Gomes A, Lima V, et al. (August 2018). "Genetic influence alters the brain synchronism in perception and timing". Journal of Biomedical Science. 25 (1): 61. doi:10.1186/s12929-018-0463-z. PMID 30086746.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Maison SF, Rosahl TW, Homanics GE, Liberman MC (October 2006). "Functional role of GABAergic innervation of the cochlea: phenotypic analysis of mice lacking GABA(A) receptor subunits alpha 1, alpha 2, alpha 5, alpha 6, beta 2, beta 3, or delta". The Journal of Neuroscience. 26 (40): 10315–26. doi:10.1523/JNEUROSCI.2395-06.2006. PMID 17021187.
- ^ Lo WS, Lau CF, Xuan Z, Chan CF, Feng GY, He L, et al. (June 2004). "Association of SNPs and haplotypes in GABAA receptor beta2 gene with schizophrenia". Molecular Psychiatry. 9 (6): 603–8. doi:10.1038/sj.mp.4001461. PMID 14699426.
- ^ Liu J, Shi Y, Tang W, Guo T, Li D, Yang Y, et al. (September 2005). "Positive association of the human GABA-A-receptor beta 2 subunit gene haplotype with schizophrenia in the Chinese Han population". Biochemical and Biophysical Research Communications. 334 (3): 817–23. doi:10.1016/j.bbrc.2005.06.167. PMID 16023997.
- ^ Lo WS, Harano M, Gawlik M, Yu Z, Chen J, Pun FW, et al. (March 2007). "GABRB2 association with schizophrenia: commonalities and differences between ethnic groups and clinical subtypes". Biological Psychiatry. 61 (5): 653–60. doi:10.1016/j.biopsych.2006.05.003. PMID 16950232.
- ^ Petryshen TL, Middleton FA, Tahl AR, Rockwell GN, Purcell S, Aldinger KA, et al. (December 2005). "Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia". Molecular Psychiatry. 10 (12): 1074–88, 1057. doi:10.1038/sj.mp.4001739. PMID 16172613.
- ^ Yu Z, Chen J, Shi H, Stoeber G, Tsang SY, Xue H (March 2006). "Analysis of GABRB2 association with schizophrenia in German population with DNA sequencing and one-label extension method for SNP genotyping". Clinical Biochemistry. 39 (3): 210–8. doi:10.1016/j.clinbiochem.2006.01.009. PMID 16472798.
- ^ Tsang SY, Zhong S, Mei L, Chen J, Ng SK, Pun FW, et al. (24 April 2013). "Social cognitive role of schizophrenia candidate gene GABRB2". PloS One. 8 (4): e62322. doi:10.1371/journal.pone.0062322. PMID 23638040.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Zhang Q, Zhang X, Song S, Wang S, Wang X, Yu H, et al. (June 2020). "The association of GABRB2 SNPs with cognitive function in schizophrenia". European Archives of Psychiatry and Clinical Neuroscience. 270 (4): 443–449. doi:10.1007/s00406-019-00985-3. PMID 30706170.
- ^ Inada T, Koga M, Ishiguro H, Horiuchi Y, Syu A, Yoshio T, et al. (April 2008). "Pathway-based association analysis of genome-wide screening data suggest that genes associated with the gamma-aminobutyric acid receptor signaling pathway are involved in neuroleptic-induced, treatment-resistant tardive dyskinesia". Pharmacogenetics and Genomics. 18 (4): 317–23. doi:10.1097/FPC.0b013e3282f70492. PMID 18334916.
- ^ Ullah A, Long X, Mat WK, Hu T, Khan MI, Hui L, et al. (30 June 2020). "Highly Recurrent Copy Number Variations in GABRB2 Associated With Schizophrenia and Premenstrual Dysphoric Disorder". Frontiers in Psychiatry. 11: 572. doi:10.3389/fpsyt.2020.00572. PMID 32695026.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Zhao C, Xu Z, Chen J, Yu Z, Tong KL, Lo WS, et al. (December 2006). "Two isoforms of GABA(A) receptor beta2 subunit with different electrophysiological properties: Differential expression and genotypical correlations in schizophrenia". Molecular Psychiatry. 11 (12): 1092–105. doi:10.1038/sj.mp.4001899. PMID 16983389.
- ^ Lo WS, Xu Z, Yu Z, Pun FW, Ng SK, Chen J, et al. (May 2007). "Positive selection within the Schizophrenia-associated GABA(A) receptor beta(2) gene". PloS One. 2 (5): e462. doi:10.1371/journal.pone.0000462. PMID 17520021.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Pun FW, Zhao C, Lo WS, Ng SK, Tsang SY, Nimgaonkar V, et al. (May 2011). "Imprinting in the schizophrenia candidate gene GABRB2 encoding GABA(A) receptor β(2) subunit". Molecular Psychiatry. 16 (5): 557–68. doi:10.1038/mp.2010.47. PMID 20404824.
- ^ Zhao C, Wang F, Pun FW, Mei L, Ren L, Yu Z, et al. (February 2012). "Epigenetic regulation on GABRB2 isoforms expression: developmental variations and disruptions in psychotic disorders". Schizophrenia Research. 134 (2–3): 260–6. doi:10.1016/j.schres.2011.11.029. PMID 22206711.
- ^ Zong L, Zhou L, Hou Y, Zhang L, Jiang W, Zhang W, et al. (May 2017). "Genetic and epigenetic regulation on the transcription of GABRB2: Genotype-dependent hydroxymethylation and methylation alterations in schizophrenia". Journal of Psychiatric Research. 88: 9–17. doi:10.1016/j.jpsychires.2016.12.019. PMID 28063323.
- ^ Mueller TM, Haroutunian V, Meador-Woodruff JH (February 2014). "N-Glycosylation of GABAA receptor subunits is altered in Schizophrenia". Neuropsychopharmacology. 39 (3): 528–37. doi:10.1038/npp.2013.190. PMID 23917429.
- ^ Lo WS, Xu Z, Yu Z, Pun FW, Ng SK, Chen J, et al. (May 2007). "Positive selection within the Schizophrenia-associated GABA(A) receptor beta(2) gene". PloS One. 2 (5): e462. doi:10.1371/journal.pone.0000462. PMID 17520021.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Yeung RK, Xiang ZH, Tsang SY, Li R, Ho TY, Li Q, et al. (July 2018). "Gabrb2-knockout mice displayed schizophrenia-like and comorbid phenotypes with interneuron-astrocyte-microglia dysregulation". Translational Psychiatry. 8 (1): 128. doi:10.1038/s41398-018-0176-9. PMID 30013074.
- ^ Zhao C, Xu Z, Wang F, Chen J, Ng SK, Wong PW, et al. (September 2009). "Alternative-splicing in the exon-10 region of GABA(A) receptor beta(2) subunit gene: relationships between novel isoforms and psychotic disorders". PloS One. 4 (9): e6977. doi:10.1371/journal.pone.0006977. PMID 19763268.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Perlis RH, Purcell S, Fagerness J, Kirby A, Petryshen TL, Fan J, Sklar P (January 2008). "Family-based association study of lithium-related and other candidate genes in bipolar disorder". Archives of General Psychiatry. 65 (1): 53–61. doi:10.1001/archgenpsychiatry.2007.15. PMID 18180429.
- ^ Breuer R, Hamshere ML, Strohmaier J, Mattheisen M, Degenhardt F, Meier S, et al. (June 2011). "Independent evidence for the selective influence of GABA(A) receptors on one component of the bipolar disorder phenotype". Molecular Psychiatry. 16 (6): 587–9. doi:10.1038/mp.2010.67. PMID 20548298.
- ^ Chen J, Tsang SY, Zhao CY, Pun FW, Yu Z, Mei L, et al. (December 2009). "GABRB2 in schizophrenia and bipolar disorder: disease association, gene expression and clinical correlations". Biochemical Society Transactions. 37 (Pt 6): 1415–8. doi:10.1042/BST0371415. PMID 19909288.
- ^ Choudary PV, Molnar M, Evans SJ, Tomita H, Li JZ, Vawter MP, et al. (October 2005). "Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression". Proceedings of the National Academy of Sciences of the United States of America. 102 (43): 15653–8. doi:10.1073/pnas.0507901102. PMID 16230605.
- ^ Zhao J, Bao AM, Qi XR, Kamphuis W, Luchetti S, Lou JS, Swaab DF (May 2012). "Gene expression of GABA and glutamate pathway markers in the prefrontal cortex of non-suicidal elderly depressed patients". Journal of Affective Disorders. 138 (3): 494–502. doi:10.1016/j.jad.2012.01.013. PMID 22357337.
- ^ Lee M, Cho H, Jung SH, Yim SH, Cho SM, Chun JW, et al. (12 March 2018). "Circulating MicroRNA Expression Levels Associated With Internet Gaming Disorder". Frontiers in Psychiatry. 9: 81. doi:10.3389/fpsyt.2018.00081. PMID 29593587.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Hofmeister S, Bodden S (August 2016). "Premenstrual Syndrome and Premenstrual Dysphoric Disorder". American Family Physician. 94 (3): 236–40. PMID 27479626.
- ^ Liu B, Wang G, Gao D, Gao F, Zhao B, Qiao M, et al. (January 2015). "Alterations of GABA and glutamate-glutamine levels in premenstrual dysphoric disorder: a 3T proton magnetic resonance spectroscopy study". Psychiatry Research. 231 (1): 64–70. doi:10.1016/j.pscychresns.2014.10.020. PMID 25465316.
- ^ Ullah A, Long X, Mat WK, Hu T, Khan MI, Hui L, et al. (30 June 2020). "Highly Recurrent Copy Number Variations in GABRB2 Associated With Schizophrenia and Premenstrual Dysphoric Disorder". Frontiers in Psychiatry. 11: 572. doi:10.3389/fpsyt.2020.00572. PMID 32695026.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Tabakoff B, Saba L, Printz M, Flodman P, Hodgkinson C, Goldman D, et al. (October 2009). "Genetical genomic determinants of alcohol consumption in rats and humans". BMC Biology. 7 (1): 70. doi:10.1186/1741-7007-7-70. PMID 19874574.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Loh EW, Smith I, Murray R, McLaughlin M, McNulty S, Ball D (November 1999). "Association between variants at the GABAAbeta2, GABAAalpha6 and GABAAgamma2 gene cluster and alcohol dependence in a Scottish population". Molecular Psychiatry. 4 (6): 539–44. doi:10.1038/sj.mp.4000554. PMID 10578235.
- ^ Radel M, Vallejo RL, Iwata N, Aragon R, Long JC, Virkkunen M, Goldman D (January 2005). "Haplotype-based localization of an alcohol dependence gene to the 5q34 {gamma}-aminobutyric acid type A gene cluster". Archives of General Psychiatry. 62 (1): 47–55. doi:10.1001/archpsyc.62.1.47. PMID 15630072.
- ^ Devaud LL, Fritschy JM, Sieghart W, Morrow AL (July 1997). "Bidirectional alterations of GABA(A) receptor subunit peptide levels in rat cortex during chronic ethanol consumption and withdrawal". Journal of Neurochemistry. 69 (1): 126–30. doi:10.1046/j.1471-4159.1997.69010126.x. PMID 9202302.
- ^ Blednov YA, Jung S, Alva H, Wallace D, Rosahl T, Whiting PJ, Harris RA (January 2003). "Deletion of the alpha1 or beta2 subunit of GABAA receptors reduces actions of alcohol and other drugs". The Journal of Pharmacology and Experimental Therapeutics. 304 (1): 30–6. doi:10.1124/jpet.102.042960. PMID 12490572.
- ^ Levran O, Peles E, Randesi M, Correa da Rosa J, Ott J, Rotrosen J, et al. (January 2016). "Glutamatergic and GABAergic susceptibility loci for heroin and cocaine addiction in subjects of African and European ancestry". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 64: 118–23. doi:10.1016/j.pnpbp.2015.08.003. PMID 26277529.
- ^ Kim YS, Yang M, Mat WK, Tsang SY, Su Z, Jiang X, et al. (12 November 2015). "GABRB2 Haplotype Association with Heroin Dependence in Chinese Population". PloS One. 10 (11): e0142049. doi:10.1371/journal.pone.0142049. PMID 26561861.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Hamdan FF, Myers CT, Cossette P, Lemay P, Spiegelman D, Laporte AD, et al. (November 2017). "High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies". American Journal of Human Genetics. 101 (5): 664–685. doi:10.1016/j.ajhg.2017.09.008. PMID 29100083.
- ^ Ishii A, Kang JQ, Schornak CC, Hernandez CC, Shen W, Watkins JC, et al. (March 2017). "A de novo missense mutation of GABRB2 causes early myoclonic encephalopathy". Journal of Medical Genetics. 54 (3): 202–211. doi:10.1136/jmedgenet-2016-104083. PMID 27789573.
- ^ May P, Girard S, Harrer M, Bobbili DR, Schubert J, Wolking S, et al. (August 2018). "Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study". The Lancet. Neurology. 17 (8): 699–708. doi:10.1016/S1474-4422(18)30215-1. PMID 30033060.
- ^ Bosch DG, Boonstra FN, de Leeuw N, Pfundt R, Nillesen WM, de Ligt J, et al. (May 2016). "Novel genetic causes for cerebral visual impairment". European Journal of Human Genetics. 24 (5): 660–5. doi:10.1038/ejhg.2015.186. PMID 26350515.
- ^ Srivastava S, Cohen J, Pevsner J, Aradhya S, McKnight D, Butler E, et al. (November 2014). "A novel variant in GABRB2 associated with intellectual disability and epilepsy". American Journal of Medical Genetics. Part A. 164A (11): 2914–21. doi:10.1002/ajmg.a.36714. PMID 25124326.
- ^ Kumari R, Lakhan R, Kalita J, Garg RK, Misra UK, Mittal B (June 2011). "Potential role of GABAA receptor subunit; GABRA6, GABRB2 and GABRR2 gene polymorphisms in epilepsy susceptibility and pharmacotherapy in North Indian population". Clinica Chimica Acta; International Journal of Clinical Chemistry. 412 (13–14): 1244–8. doi:10.1016/j.cca.2011.03.018. PMID 21420396.
- ^ Yeung RK, Xiang ZH, Tsang SY, Li R, Ho TY, Li Q, et al. (July 2018). "Gabrb2-knockout mice displayed schizophrenia-like and comorbid phenotypes with interneuron-astrocyte-microglia dysregulation". Translational Psychiatry. 8 (1): 128. doi:10.1038/s41398-018-0176-9. PMID 30013074.
- ^ Blatt GJ, Fitzgerald CM, Guptill JT, Booker AB, Kemper TL, Bauman ML (December 2001). "Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study". Journal of Autism and Developmental Disorders. 31 (6): 537–43. doi:10.1023/a:1013238809666. PMID 11814263.
- ^ Ma DQ, Whitehead PL, Menold MM, Martin ER, Ashley-Koch AE, Mei H, et al. (September 2005). "Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism". American Journal of Human Genetics. 77 (3): 377–88. doi:10.1086/433195. PMID 16080114.
- ^ Cogliati F, Giorgini V, Masciadri M, Bonati MT, Marchi M, Cracco I, et al. (July 2019). "Pathogenic Variants in STXBP1 and in Genes for GABAa Receptor Subunities Cause Atypical Rett/Rett-like Phenotypes". International Journal of Molecular Sciences. 20 (15): 3621. doi:10.3390/ijms20153621. PMID 31344879.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Sajan SA, Jhangiani SN, Muzny DM, Gibbs RA, Lupski JR, Glaze DG, et al. (January 2017). "Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2". Genetics in Medicine. 19 (1): 13–19. doi:10.1038/gim.2016.42. PMID 27171548.
- ^ Chen CY, Di Lucente J, Lin YC, Lien CC, Rogawski MA, Maezawa I, Jin LW (January 2018). "Defective GABAergic neurotransmission in the nucleus tractus solitarius in Mecp2-null mice, a model of Rett syndrome". Neurobiology of Disease. 109 (Pt A): 25–32. doi:10.1016/j.nbd.2017.09.006. PMID 28927958.
- ^ Li Y, Sun H, Chen Z, Xu H, Bu G, Zheng H (23 February 2016). "Implications of GABAergic Neurotransmission in Alzheimer's Disease". Frontiers in Aging Neuroscience. 8: 31. doi:10.3389/fnagi.2016.00031. PMID 26941642.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Li JQ, Yuan XZ, Li HY, Cao XP, Yu JT, Tan L, Chen WA (May 2018). "Genome-wide association study identifies two loci influencing plasma neurofilament light levels". BMC Medical Genomics. 11 (1): 47. doi:10.1186/s12920-018-0364-8. PMID 29747637.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Jiang S, Wen N, Li Z, Dube U, Del Aguila J, Budde J, et al. (December 2018). "Integrative system biology analyses of CRISPR-edited iPSC-derived neurons and human brains reveal deficiencies of presynaptic signaling in FTLD and PSP". Translational Psychiatry. 8 (1): 265. doi:10.1038/s41398-018-0319-z. PMID 30546007.
- ^ Matarin M, Salih DA, Yasvoina M, Cummings DM, Guelfi S, Liu W, et al. (February 2015). "A genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology". Cell Reports. 10 (4): 633–44. doi:10.1016/j.celrep.2014.12.041. PMID 25620700.
- ^ Wiseman SM, Haddad Z, Walker B, Vergara IA, Sierocinski T, Crisan A, et al. (October 2013). "Whole-transcriptome profiling of thyroid nodules identifies expression-based signatures for accurate thyroid cancer diagnosis". The Journal of Clinical Endocrinology and Metabolism. 98 (10): 4072–9. doi:10.1210/jc.2013-1991. PMID 23928671.
- ^ Alexander EK, Kennedy GC, Baloch ZW, Cibas ES, Chudova D, Diggans J, et al. (August 2012). "Preoperative diagnosis of benign thyroid nodules with indeterminate cytology". The New England Journal of Medicine. 367 (8): 705–15. doi:10.1056/NEJMoa1203208. PMID 22731672.
- ^ Barros-Filho MC, Marchi FA, Pinto CA, Rogatto SR, Kowalski LP (June 2015). "High Diagnostic Accuracy Based on CLDN10, HMGA2, and LAMB3 Transcripts in Papillary Thyroid Carcinoma". The Journal of Clinical Endocrinology and Metabolism. 100 (6): E890-9. doi:10.1210/jc.2014-4053. PMID 25867809.
- ^ Wang QX, Chen ED, Cai YF, Li Q, Jin YX, Jin WX, et al. (October 2016). "A panel of four genes accurately differentiates benign from malignant thyroid nodules". Journal of Experimental & Clinical Cancer Research. 35 (1): 169. doi:10.1186/s13046-016-0447-3. PMID 27793213.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Beltrami CM, Dos Reis MB, Barros-Filho MC, Marchi FA, Kuasne H, Pinto CA, et al. (December 2017). "Integrated data analysis reveals potential drivers and pathways disrupted by DNA methylation in papillary thyroid carcinomas". Clinical Epigenetics. 9 (1): 45. doi:10.1186/s13148-017-0346-2. PMID 28469731.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Jin Y, Jin W, Zheng Z, Chen E, Wang Q, Wang Y, et al. (October 2017). "GABRB2 plays an important role in the lymph node metastasis of papillary thyroid cancer". Biochemical and Biophysical Research Communications. 492 (3): 323–330. doi:10.1016/j.bbrc.2017.08.114. PMID 28859983.
- ^ Knott EL, Leidenheimer NJ (November 2020). "A Targeted Bioinformatics Assessment of Adrenocortical Carcinoma Reveals Prognostic Implications of GABA System Gene Expression". International Journal of Molecular Sciences. 21 (22). doi:10.3390/ijms21228485. PMID 33187258.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Chen W, Liu BY, Zhang X, Zhao XG, Cao G, Dong Z, Zhang SL (August 2016). "Identification of differentially expressed genes in salivary adenoid cystic carcinoma cells associated with metastasis". Archives of Medical Science. 12 (4): 881–8. doi:10.5114/aoms.2016.60973. PMID 27478471.
- ^ Gross AM, Kreisberg JF, Ideker T (10 November 2015). "Analysis of Matched Tumor and Normal Profiles Reveals Common Transcriptional and Epigenetic Signals Shared across Cancer Types". PloS One. 10 (11): e0142618. doi:10.1371/journal.pone.0142618. PMID 26555223.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Liu A, Zhao H, Sun B, Han X, Zhou D, Cui Z, et al. (March 2020). "A predictive analysis approach for paediatric and adult high-grade glioma: miRNAs and network insight". Annals of Translational Medicine. 8 (5): 242. doi:10.21037/atm.2020.01.12. PMID 32309389.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Liu BX, Huang GJ, Cheng HB (November 2019). "Comprehensive Analysis of Core Genes and Potential Mechanisms in Rectal Cancer". Journal of Computational Biology. 26 (11): 1262–1277. doi:10.1089/cmb.2019.0073. PMID 31211595.
- ^ Markert JM, Fuller CM, Gillespie GY, Bubien JK, McLean LA, Hong RL, et al. (February 2001). "Differential gene expression profiling in human brain tumors". Physiological Genomics. 5 (1): 21–33. doi:10.1152/physiolgenomics.2001.5.1.21. PMID 11161003.
- ^ Narasimhan K, Gauthaman K, Pushparaj PN, Meenakumari G, Chaudhary AG, Abuzenadah A, et al. (22 April 2014). "Identification of Unique miRNA Biomarkers in Colorectal Adenoma and Carcinoma Using Microarray: Evaluation of Their Putative Role in Disease Progression". ISRN Cell Biology. 2014: 1–10. doi:10.1155/2014/526075.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Yan L, Gong YZ, Shao MN, Ruan GT, Xie HL, Liao XW, et al. (July 2020). "Distinct diagnostic and prognostic values of γ-aminobutyric acid type A receptor family genes in patients with colon adenocarcinoma". Oncology Letters. 20 (1): 275–291. doi:10.3892/ol.2020.11573. PMID 32565954.
- ^ Hartiadi LY, Ahring PK, Chebib M, Absalom NL (March 2016). "High and low GABA sensitivity α4β2δ GABAA receptors are expressed in Xenopus laevis oocytes with divergent stoichiometries". Biochemical Pharmacology. 103: 98–108. doi:10.1016/j.bcp.2015.12.021. PMID 26774457.
- ^ Laha KT, Tran PN (January 2013). "Multiple tyrosine residues at the GABA binding pocket influence surface expression and mediate kinetics of the GABAA receptor". Journal of Neurochemistry. 124 (2): 200–9. doi:10.1111/jnc.12083. PMID 23121119.
- ^ Tierney ML, Luu T, Gage PW (January 2008). "Functional asymmetry of the conserved cystine loops in alphabetagamma GABA A receptors revealed by the response to GABA activation and drug potentiation". The International Journal of Biochemistry & Cell Biology. 40 (5): 968–79. doi:10.1016/j.biocel.2007.10.029. PMID 18083058.
- ^ McCracken ML, Borghese CM, Trudell JR, Harris RA (December 2010). "A transmembrane amino acid in the GABAA receptor β2 subunit critical for the actions of alcohols and anesthetics". The Journal of Pharmacology and Experimental Therapeutics. 335 (3): 600–6. doi:10.1124/jpet.110.170472. PMID 20826568.
- ^ Cirone J, Rosahl TW, Reynolds DS, Newman RJ, O'Meara GF, Hutson PH, Wafford KA (June 2004). "Gamma-aminobutyric acid type A receptor beta 2 subunit mediates the hypothermic effect of etomidate in mice". Anesthesiology. 100 (6): 1438–45. doi:10.1097/00000542-200406000-00016. PMID 15166563.
- ^ Groves JO, Guscott MR, Hallett DJ, Rosahl TW, Pike A, Davies A, et al. (July 2006). "The role of GABAbeta2 subunit-containing receptors in mediating the anticonvulsant and sedative effects of loreclezole". The European Journal of Neuroscience. 24 (1): 167–74. doi:10.1111/j.1460-9568.2006.04890.x. PMID 16882014.
- ^ Baur R, Kielar M, Richter L, Ernst M, Ecker GF, Sigel E (July 2013). "Molecular analysis of the site for 2-arachidonylglycerol (2-AG) on the β₂ subunit of GABA(A) receptors". Journal of Neurochemistry. 126 (1): 29–36. doi:10.1111/jnc.12270. PMID 23600744.
- ^ Li X, Yang Q, Hu Y (January 2006). "Regulation of the expression of GABAA receptor subunits by an antiepileptic drug QYS". Neuroscience Letters. 392 (1–2): 145–9. doi:10.1016/j.neulet.2005.09.011. PMID 16214289.
- ^ Zhang Y, Mayer-Blackwell B, Schlussman SD, Randesi M, Butelman ER, Ho A, et al. (April 2014). "Extended access oxycodone self-administration and neurotransmitter receptor gene expression in the dorsal striatum of adult C57BL/6 J mice". Psychopharmacology. 231 (7): 1277–87. doi:10.1007/s00213-013-3306-3. PMID 24221825.
External links
- GABRB2+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: P47870 (Gamma-aminobutyric acid receptor subunit beta-2) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
 | This membrane protein–related article is a stub. You can help Wikipedia by expanding it. |