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Glutamate decarboxylase

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glutamate decarboxylase
Identifiers
EC no.4.1.1.15
CAS no.9024-58-2m
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins
Glutamic acid decarboxylase 1
GAD67 derived from PDB: 2okj​
Identifiers
SymbolGAD1
Alt. symbolsglutamate decarboxylase 1
(brain, 67kD); GAD67
NCBI gene2571
HGNC4092
OMIM605363
RefSeqNM_000817
UniProtQ99259
Other data
EC number4.1.1.15
LocusChr. 2 q31
Search for
StructuresSwiss-model
DomainsInterPro
glutamic acid decarboxylase 2
Identifiers
SymbolGAD2
Alt. symbolsGAD65
NCBI gene2572
HGNC11284
OMIM4093
RefSeqNM_001047
UniProtQ05329
Other data
EC number4.1.1.15
LocusChr. 10 p11.23
Search for
StructuresSwiss-model
DomainsInterPro

Glutamate decarboxylase or glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the decarboxylation of glutamate to GABA and CO2. GAD uses PLP as a cofactor. The reaction proceeds as follows:

HOOC-CH2-CH2-CH(NH2)-COOH → CO2 + HOOC-CH2-CH2-CH2NH2

In mammals, GAD exists in two isoforms with molecular weights of 67 and 65 kDa (GAD67 and GAD65), which are encoded by two different genes on different chromosomes (GAD1 and GAD2 genes, respectively).[1] GAD67 and GAD65 are expressed in the brain where GABA is used as a neurotransmitter, and they are also expressed in the insulin-producing β-cells of the pancreas, in varying ratios depending upon the species.[2]

Several truncated transcripts and polypeptides of GAD67 are detectable in the developing brain,[3] however their function, if any, is unknown.

Regulation of GAD65 and GAD67

GAD65 and GAD67 synthesize GABA at different locations in the cell, at different developmental times, and for functionally different purposes.[4][5] GAD67 is spread evenly throughout the cell while GAD65 is localized to nerve terminals.[4][6][7] This difference is thought to reflect a functional difference; GAD67 synthesizes GABA for neuron activity unrelated to neurotransmission, such as synaptogenesis and protection from neural injury.[4][5] This function requires widespread, ubiquitous presence of GABA. GAD65, however, synthesizes GABA for neurotransmission,[4] and therefore is only necessary at nerve terminals and synapses. In order to aid in neurotransmission, GAD65 forms a complex with Heat Shock Cognate 70 (HSC70), cysteine string protein (CSP) and Vesicular GABA transporter VGAT, which, as a complex, helps package GABA into vesicles for release during neurotransmission.[8] GAD67 is transcribed during early development, while GAD65 is not transcribed until later in life.[4] This developmental difference in GAD67 and GAD65 reflects the functional properties of each isoform; GAD67 is needed throughout development for normal cellular functioning, while GAD65 is not needed until slightly later in development when synaptic inhibition is more prevalent.[4]

GAD67 and GAD65 are also regulated differently post-translationally. Both GAD65 and GAD67 are regulated via phosphorylation,[9] but the regulation of these isoforms differs; GAD65 is activated by phosphorylation while GAD67 is inhibited by phosphorylation. GAD67 is phosphorylated at threonine 91 by protein kinase A (PKA), while GAD65 is phosphorylated, and therefore regulated by, protein kinase C (PKC). Both GAD67 and GAD65 are also regulated post-translationally by Pyridoxal 5’-phosphate (PLP); GAD is activated when bound to PLP and inactive when not bound to PLP.[10] Majority of GAD67 is bound to PLP at any given time, whereas GAD65 binds PLP when GABA is needed for neurotransmission.[10] This reflects the functional properties of the two isoforms; GAD67 must be active at all times for normal cellular functioning, and is therefore constantly activated by PLP, while GAD65 must only be activated when GABA neurotransmission occurs, and is therefore regulated according to the synaptic environment.

Role in pathology

Diabetes

Both GAD67 and GAD65 are targets of autoantibodies in people who later develop type 1 diabetes mellitus or latent autoimmune diabetes.[11][12] Injections with GAD65 in ways that induce immune tolerance have been shown to prevent type 1 diabetes in rodent models.[13][14][15] In clinical trials, injections with GAD65 have been shown to preserve some insulin production for 30 months in humans with type 1 diabetes.[16][17]

Stiff person syndrome

High titers of autoantibodies to glutamic acid decarboxylase (GAD) are well documented in association with stiff person syndrome (SPS). Glutamic acid decarboxylase is the rate-limiting enzyme in the synthesis of γ-aminobutyric acid (GABA), and impaired function of GABAergic neurons has been implicated in the pathogenesis of SPS. Autoantibodies to GAD might be the causative agent or a disease marker.[18]

Schizophrenia and bipolar disorder

Substantial dysregulation of GAD mRNA expression, coupled with downregulation of reelin, is observed in schizophrenia and bipolar disorder.[19] The most pronounced downregulation of GAD67 was found in hippocampal stratum oriens layer in both disorders and in other layers and structures of hippocampus with varying degrees.[20]

GAD67 is a key enzyme involved in the synthesis of inhibitory neurotransmitter GABA and people with schizophrenia have been shown to express lower amounts of GAD67 in the dorsolateral prefrontal cortex compared to healthy controls.[21] The mechanism underlying the decreased levels of GAD67 in people with schizophrenia remains unclear. Some have proposed that an immediate early gene, Zif268, which normally binds to the promoter region of GAD67 and increases transcription of GAD67, is lower in schizophrenic patients, thus contributing to decreased levels of GAD67.[21] Since the dorsolateral prefrontal cortex (DLPFC) is involved in working memory, and GAD67 and Zif268 mRNA levels are lower in the DLPFC of schizophrenic patients, this molecular alteration may account, at least in part, for the working memory impairments associated with the disease.

Parkinson disease

The bilateral delivery of glutamic acid decarboxylase (GAD) by an adeno-associated viral vector into the subthalamic nucleus of patients between 30 and 75 years of age with advanced, progressive, levodopa-responsive Parkinson disease resulted in significant improvement over baseline during the course of a six-month study.[22]

Cerebellar disorders

Intracerebellar administration of GAD autoantibodies to animals increases the excitability of motoneurons and impairs the production of nitric oxide (NO), a molecule involved in learning. Epitope recognition contributes to cerebellar involvement.[23] Reduced GABA levels increase glutamate levels as a consequence of lower inhibition of subtypes of GABA receptors. Higher glutamate levels activate microglia and activation of xc(−) increases the extracellular glutamate release.[24]

Neuropathic pain

Peripheral nerve injury of the sciatic nerve (a neuropathic pain model) induces a transient loss of GAD65 immunoreactive terminals in the spinal cord dorsal horn and suggests a potential involvement for these alterations in the development and amelioration of pain behaviour.[25]

Other Anti-GAD-associated neurologic disorders

Antibodies directed against glutamic acid decarboxylase (GAD) are increasingly found in patients with other symptoms indicative of central nervous system (CNS) dysfunction, such as ataxia, progressive encephalomyelitis with rigidity and myoclonus (PERM), limbic encephalitis, and epilepsy.[26] The pattern of anti-GAD antibodies in epilepsy differs from type 1 diabetes and stiff-person syndrome.[27]

References

  1. ^ Erlander MG, Tillakaratne NJ, Feldblum S, Patel N, Tobin AJ (July 1991). "Two genes encode distinct glutamate decarboxylases". Neuron. 7 (1): 91–100. doi:10.1016/0896-6273(91)90077-D. PMID 2069816.
  2. ^ Kim J, Richter W, Aanstoot HJ, Shi Y, Fu Q, Rajotte R, Warnock G, Baekkeskov S (1993). "Differential expression of GAD65 and GAD67 in human, rat, and mouse pancreatic islets". Diabetes. 42 (12): 1799–808. doi:10.2337/diab.42.12.1799. PMID 8243826.
  3. ^ Szabo G, Katarova Z, Greenspan R (November 1994). "Distinct protein forms are produced from alternatively spliced bicistronic glutamic acid decarboxylase mRNAs during development". Molecular and Cellular Biology. 14 (11): 7535–45. doi:10.1128/mcb.14.11.7535. PMC 359290. PMID 7935469.
  4. ^ a b c d e f Pinal CS, Tobin AJ (1998). "Uniqueness and redundancy in GABA production". Perspectives on Developmental Neurobiology. 5 (2–3): 109–18. PMID 9777629.
  5. ^ a b Soghomonian JJ, Martin DL (1998). "Two isoforms of glutamate decarboxylase: why?". Trends Pharmacol. Sci. 19 (12): 500–5. doi:10.1016/s0165-6147(98)01270-x. PMID 9871412.
  6. ^ Kaufman DL, Houser CR, Tobin AJ (1991). "Two forms of the gamma-aminobutyric acid synthetic enzyme glutamate decarboxylase have distinct intraneuronal distributions and cofactor interactions". J. Neurochem. 56 (2): 720–3. doi:10.1111/j.1471-4159.1991.tb08211.x. PMID 1988566.
  7. ^ Kanaani J, Cianciaruso C, Phelps EA, Pasquier M, Brioudes E, Billestrup N, Baekkeskov S (2015). "Compartmentalization of GABA synthesis by GAD67 differs between pancreatic beta cells and neurons". PLoS ONE. 10 (2): e0117130. doi:10.1371/journal.pone.0117130. PMC 4315522. PMID 25647668.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  8. ^ Jin H, Wu H, Osterhaus G, Wei J, Davis K, Sha D, Floor E, Hsu CC, Kopke RD, Wu JY (April 2003). "Demonstration of functional coupling between gamma -aminobutyric acid (GABA) synthesis and vesicular GABA transport into synaptic vesicles". Proceedings of the National Academy of Sciences of the United States of America. 100 (7): 4293–8. doi:10.1073/pnas.0730698100. PMC 153086. PMID 12634427.
  9. ^ Wei J, Davis KM, Wu H, Wu JY (May 2004). "Protein phosphorylation of human brain glutamic acid decarboxylase (GAD)65 and GAD67 and its physiological implications". Biochemistry. 43 (20): 6182–9. doi:10.1021/bi0496992. PMID 15147202.
  10. ^ a b Battaglioli G, Liu H, Martin DL (August 2003). "Kinetic differences between the isoforms of glutamate decarboxylase: implications for the regulation of GABA synthesis". Journal of Neurochemistry. 86 (4): 879–87. doi:10.1046/j.1471-4159.2003.01910.x. PMID 12887686.
  11. ^ Baekkeskov S, Aanstoot HJ, Christgau S, Reetz A, Solimena M, Cascalho M, Folli F, Richter-Olesen H, De Camilli P, Camilli PD (September 1990). "Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase". Nature. 347 (6289): 151–6. doi:10.1038/347151a0. PMID 1697648.
  12. ^ Kaufman DL, Erlander MG, Clare-Salzler M, Atkinson MA, Maclaren NK, Tobin AJ (January 1992). "Autoimmunity to two forms of glutamate decarboxylase in insulin-dependent diabetes mellitus". The Journal of Clinical Investigation. 89 (1): 283–92. doi:10.1172/JCI115573. PMC 442846. PMID 1370298.
  13. ^ Tisch R, Yang XD, Singer SM, Liblau RS, Fugger L, McDevitt HO (1993). "Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice". Nature. 366 (6450): 72–5. doi:10.1038/366072a0. PMID 8232539.
  14. ^ Kaufman DL, Clare-Salzler M, Tian J, Forsthuber T, Ting GS, Robinson P, Atkinson MA, Sercarz EE, Tobin AJ, Lehmann PV (1993). "Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes". Nature. 366 (6450): 69–72. doi:10.1038/366069a0. PMID 7694152.
  15. ^ Tian J, Clare-Salzler M, Herschenfeld A, Middleton B, Newman D, Mueller R, Arita S, Evans C, Atkinson MA, Mullen Y, Sarvetnick N, Tobin AJ, Lehmann PV, Kaufman DL (1996). "Modulating autoimmune responses to GAD inhibits disease progression and prolongs islet graft survival in diabetes-prone mice". Nat. Med. 2 (12): 1348–53. doi:10.1038/nm1296-1348. PMID 8946834.
  16. ^ Ludvigsson J, Faresjö M, Hjorth M, Axelsson S, Chéramy M, Pihl M, Vaarala O, Forsander G, Ivarsson S, Johansson C, Lindh A, Nilsson NO, Aman J, Ortqvist E, Zerhouni P, Casas R (October 2008). "GAD treatment and insulin secretion in recent-onset type 1 diabetes". The New England Journal of Medicine. 359 (18): 1909–20. doi:10.1056/NEJMoa0804328. PMID 18843118.
  17. ^ "Diamyd announces completion of type 1 diabetes vaccine trial with long term efficacy demonstrated at 30 months". Press Release. Diamyd Medical AB. 2008-01-28. Retrieved 2010-01-13.
  18. ^ Chang T, Alexopoulos H, McMenamin M, Carvajal-González A, Alexander SK, Deacon R, Erdelyi F, Szabó G, Gabor S, Lang B, Blaes F, Brown P, Vincent A (September 2013). "Neuronal surface and glutamic acid decarboxylase autoantibodies in Nonparaneoplastic stiff person syndrome". JAMA Neurology. 70 (9): 1140–9. doi:10.1001/jamaneurol.2013.3499. PMID 23877118.
  19. ^ Woo TU, Walsh JP, Benes FM (July 2004). "Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-D-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder". Archives of General Psychiatry. 61 (7): 649–57. doi:10.1001/archpsyc.61.7.649. PMID 15237077.
  20. ^ Benes FM, Lim B, Matzilevich D, Walsh JP, Subburaju S, Minns M (June 2007). "Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars". Proceedings of the National Academy of Sciences of the United States of America. 104 (24): 10164–9. doi:10.1073/pnas.0703806104. PMC 1888575. PMID 17553960.
  21. ^ a b Kimoto S, Bazmi HH, Lewis DA (September 2014). "Lower expression of glutamic acid decarboxylase 67 in the prefrontal cortex in schizophrenia: contribution of altered regulation by Zif268". The American Journal of Psychiatry. 171 (9): 969–78. doi:10.1176/appi.ajp.2014.14010004. PMC 4376371. PMID 24874453.
  22. ^ LeWitt PA, Rezai AR, Leehey MA, Ojemann SG, Flaherty AW, Eskandar EN, Kostyk SK, Thomas K, Sarkar A, Siddiqui MS, Tatter SB, Schwalb JM, Poston KL, Henderson JM, Kurlan RM, Richard IH, Van Meter L, Sapan CV, During MJ, Kaplitt MG, Feigin A (April 2011). "AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial". The Lancet. Neurology. 10 (4): 309–19. doi:10.1016/S1474-4422(11)70039-4. PMID 21419704.
  23. ^ Manto MU, Hampe CS, Rogemond V, Honnorat J (February 2011). "Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia". Orphanet Journal of Rare Diseases. 6 (3): 3. doi:10.1186/1750-1172-6-3. PMC 3042903. PMID 21294897.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  24. ^ Mitoma H, Manto M, Hampe CS (2017-03-12). "Pathogenic Roles of Glutamic Acid Decarboxylase 65 Autoantibodies in Cerebellar Ataxias". Journal of Immunology Research. 2017: 2913297. doi:10.1155/2017/2913297. PMID 28386570.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  25. ^ Lorenzo LE, Magnussen C, Bailey AL, St Louis M, De Koninck Y, Ribeiro-da-Silva A (September 2014). "Spatial and temporal pattern of changes in the number of GAD65-immunoreactive inhibitory terminals in the rat superficial dorsal horn following peripheral nerve injury". Molecular Pain. 10 (1): 57. doi:10.1186/1744-8069-10-57. PMC 4164746. PMID 25189404.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  26. ^ Dayalu P, Teener JW (November 2012). "Stiff Person syndrome and other anti-GAD-associated neurologic disorders". Seminars in Neurology. 32 (5): 544–9. doi:10.1055/s-0033-1334477. PMID 23677666.
  27. ^ Liimatainen S, Honnorat J, Pittock SJ, McKeon A, Manto M, Radtke JR, Hampe CS (April 2018). "GAD65 autoantibody characteristics in patients with co-occurring type 1 diabetes and epilepsy may help identify underlying epilepsy etiologies". Orphanet Journal of Rare Diseases. 13 (1): 55. doi:10.1186/s13023-018-0787-5. PMC 5892043. PMID 29636076.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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