Beta-2 adrenergic receptor

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Adrenoceptor beta 2, surface
2RH1.png
Crystallographic structure of the ?2-adrenergic receptor depicted as a green cartoon and the bound partial inverse agonist carazolol ligand as spheres (carbon atom = grey, oxygen = red, nitrogen = blue). The phospholipid bilayer is depicted as blue spheres (phosphate head groups) and yellow lines (lipid sidechains).[1][2]
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols ADRB2 ; ADRB2R; ADRBR; B2AR; BAR; BETA2AR
External IDs OMIM109690 MGI87938 HomoloGene30948 IUPHAR: 29 ChEMBL: 210 GeneCards: ADRB2 Gene
RNA expression pattern
PBB GE ADRB2 206170 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 154 11555
Ensembl ENSG00000169252 ENSMUSG00000045730
UniProt P07550 P18762
RefSeq (mRNA) NM_000024 NM_007420
RefSeq (protein) NP_000015 NP_031446
Location (UCSC) Chr 5:
148.21 – 148.21 Mb
Chr 18:
62.18 – 62.18 Mb
PubMed search [1] [2]

The beta-2 adrenergic receptor2 adrenoreceptor), also known as ADRB2, is a beta-adrenergic receptor within a cell membrane which reacts with adrenaline (epinephrine) as a hormone or neurotransmitter affecting muscles or organs. The official symbol for the human gene encoding the β2 adrenoreceptor is ADRB2.[3]


Gene[edit]

The ADRB2 gene is intronless. Different polymorphic forms, point mutations, and/or downregulation of this gene are associated with nocturnal asthma, obesity and type 2 diabetes.[4]

Structure[edit]

The 3D crystallographic structure (see figure and links to the right) of the β2-adrenergic receptor has been determined[5][1][2] by making a fusion protein with lysozyme to increase the hydrophillic surface area of the protein for crystal contacts.

Mechanism[edit]

This receptor is directly associated with one of its ultimate effectors, the class C L-type calcium channel CaV1.2. This receptor-channel complex is coupled to the Gs G protein, which activates adenylyl cyclase, catalysing the formation of cyclic adenosine monophosphate (cAMP) which then activates protein kinase A, and the counterbalancing phosphatase PP2A. The assembly of the signaling complex provides a mechanism that ensures specific and rapid signaling. A two-state biophysical and molecular model has been proposed to account for the pH and REDOX sensitivity of this and other GPCRs.[6]

Beta-2 Adrenergic Receptors have also been found to couple with Gi, possibly providing a mechanism by which response to ligand is highly localized within cells. In contrast, Beta-1 Adrenergic Receptors are coupled only to Gs, and stimulation of these results in a more diffuse cellular response.[7] This appears to be mediated by cAMP induced PKA phosphorylation of the receptor.[8]

Function[edit]

Actions of the β2 receptor include:

Muscular system[edit]

Tissue/Effect Function

Smooth muscle relaxation in:

uterus

inhibits labor
GI tract (decreases motility) Delay digestion during fight-or-flight response

detrusor urinae muscle of bladder wall[9] This effect is stronger than the alpha-1 receptor effect of contraction.

Delay need of micturition
seminal tract[10]
bronchi[11] Facilitate respiration (agonists can be useful in treating asthma)

blood vessels

Increase perfusion of target organs needed during fight-or-flight
striated muscle Tremor[10] (via PKA mediated facilitation of presynaptic Ca2+ influx leading to acetylcholine release)
Increased mass and contraction speed[10] fight-or-flight
glycogenolysis[10] provide glucose fuel
pancreas Insulin secretion increases uptake of glucose by muscle

Circulatory system[edit]

Eye[edit]

In the normal eye, beta-2 stimulation by salbutamol increases intraocular pressure via net:

In glaucoma, drainage is reduced ( open-angle glaucoma) or blocked completely (closed-angle glaucoma). In such cases, beta-2 stimulation with its consequent increase in humour production is highly contra-indicated, and conversely, a topical beta-2 antagonist such as timolol may be employed.

Digestive system[edit]

Other[edit]

Agonists[edit]

Antagonists[edit]

(Beta blockers)

* denotes selective agonists to the receptor.

Interactions[edit]

Beta-2 adrenergic receptor has been shown to interact with:

See also[edit]

References[edit]

  1. ^ a b PDB 2RH1; Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC (2007). "High-resolution crystal structure of an engineered human ?2-adrenergic G protein-coupled receptor". Science 318 (5854): 1258–65. doi:10.1126/science.1150577. PMC 2583103. PMID 17962520. 
  2. ^ a b Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK (2007). "GPCR engineering yields high-resolution structural insights into ?2-adrenergic receptor function". Science 318 (5854): 1266–73. doi:10.1126/science.1150609. PMID 17962519. 
  3. ^ "Entrez Gene: ADRB2 adrenoceptor beta 2, surface". Retrieved 8 February 2015. 
  4. ^ "Entrez Gene: ADRB2 adrenergic, beta-2-, receptor, surface". 
  5. ^ Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC et al. (Nov 2007). "Crystal structure of the human beta2 adrenergic G-protein-coupled receptor". Nature 450 (7168): 383–7. Bibcode:2007Natur.450..383R. doi:10.1038/nature06325. PMID 17952055. 
  6. ^ Rubenstein LA, Zauhar RJ, Lanzara RG (Dec 2006). "Molecular dynamics of a biophysical model for beta2-adrenergic and G protein-coupled receptor activation". Journal of Molecular Graphics & Modelling 25 (4): 396–409. doi:10.1016/j.jmgm.2006.02.008. PMID 16574446. 
  7. ^ Chen-Izu Y, Xiao RP, Izu LT, Cheng H, Kuschel M, Spurgeon H et al. (Nov 2000). "G(i)-dependent localization of beta(2)-adrenergic receptor signaling to L-type Ca(2+) channels". Biophysical Journal 79 (5): 2547–56. Bibcode:2000BpJ....79.2547C. doi:10.1016/S0006-3495(00)76495-2. PMC 1301137. PMID 11053129. 
  8. ^ Zamah AM, Delahunty M, Luttrell LM, Lefkowitz RJ (Aug 2002). "Protein kinase A-mediated phosphorylation of the beta 2-adrenergic receptor regulates its coupling to Gs and Gi. Demonstration in a reconstituted system". The Journal of Biological Chemistry 277 (34): 31249–56. doi:10.1074/jbc.M202753200. PMID 12063255. 
  9. ^ von Heyden B, Riemer RK, Nunes L, Brock GB, Lue TF, Tanagho EA (1995). "Response of guinea pig smooth and striated urethral sphincter to cromakalim, prazosin, nifedipine, nitroprusside, and electrical stimulation". Neurourology and Urodynamics 14 (2): 153–68. doi:10.1002/nau.1930140208. PMID 7540086. 
  10. ^ a b c d e Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4.  Page 163
  11. ^ a b c d e f Fitzpatrick, David; Purves, Dale; Augustine, George (2004). "Table 20:2". Neuroscience (Third ed.). Sunderland, Mass: Sinauer. ISBN 0-87893-725-0. 
  12. ^ Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4.  Page 270
  13. ^ Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES (Dec 2000). "The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system". Pharmacological Reviews 52 (4): 595–638. PMID 11121511. 
  14. ^ Fan G, Shumay E, Wang H, Malbon CC (Jun 2001). "The scaffold protein gravin (cAMP-dependent protein kinase-anchoring protein 250) binds the beta 2-adrenergic receptor via the receptor cytoplasmic Arg-329 to Leu-413 domain and provides a mobile scaffold during desensitization". The Journal of Biological Chemistry 276 (26): 24005–14. doi:10.1074/jbc.M011199200. PMID 11309381. 
  15. ^ Shih M, Lin F, Scott JD, Wang HY, Malbon CC (Jan 1999). "Dynamic complexes of beta2-adrenergic receptors with protein kinases and phosphatases and the role of gravin". The Journal of Biological Chemistry 274 (3): 1588–95. doi:10.1074/jbc.274.3.1588. PMID 9880537. 
  16. ^ McVey M, Ramsay D, Kellett E, Rees S, Wilson S, Pope AJ et al. (Apr 2001). "Monitoring receptor oligomerization using time-resolved fluorescence resonance energy transfer and bioluminescence resonance energy transfer. The human delta -opioid receptor displays constitutive oligomerization at the cell surface, which is not regulated by receptor occupancy". The Journal of Biological Chemistry 276 (17): 14092–9. doi:10.1074/jbc.M008902200. PMID 11278447. 
  17. ^ Karoor V, Wang L, Wang HY, Malbon CC (Dec 1998). "Insulin stimulates sequestration of beta-adrenergic receptors and enhanced association of beta-adrenergic receptors with Grb2 via tyrosine 350". The Journal of Biological Chemistry 273 (49): 33035–41. doi:10.1074/jbc.273.49.33035. PMID 9830057. 
  18. ^ Temkin P, Lauffer B, Jäger S, Cimermancic P, Krogan NJ, von Zastrow M (Jun 2011). "SNX27 mediates retromer tubule entry and endosome-to-plasma membrane trafficking of signalling receptors". Nature Cell Biology 13 (6): 715–21. doi:10.1038/ncb2252. PMC 3113693. PMID 21602791. 
  19. ^ Karthikeyan S, Leung T, Ladias JA (May 2002). "Structural determinants of the Na+/H+ exchanger regulatory factor interaction with the beta 2 adrenergic and platelet-derived growth factor receptors". The Journal of Biological Chemistry 277 (21): 18973–8. doi:10.1074/jbc.M201507200. PMID 11882663. 
  20. ^ Hall RA, Ostedgaard LS, Premont RT, Blitzer JT, Rahman N, Welsh MJ et al. (Jul 1998). "A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins". Proceedings of the National Academy of Sciences of the United States of America 95 (15): 8496–501. doi:10.1073/pnas.95.15.8496. PMC 21104. PMID 9671706. 
  21. ^ Hall RA, Premont RT, Chow CW, Blitzer JT, Pitcher JA, Claing A et al. (Apr 1998). "The beta2-adrenergic receptor interacts with the Na+/H+-exchanger regulatory factor to control Na+/H+ exchange". Nature 392 (6676): 626–30. doi:10.1038/33458. PMID 9560162. 

Further reading[edit]

  • Frielle T, Caron MG, Lefkowitz RJ (May 1989). "Properties of the beta 1- and beta 2-adrenergic receptor subtypes revealed by molecular cloning". Clinical Chemistry 35 (5): 721–5. PMID 2541947. 
  • Taylor DR, Kennedy MA (2002). "Genetic variation of the beta(2)-adrenoceptor: its functional and clinical importance in bronchial asthma". American Journal of Pharmacogenomics : Genomics-Related Research in Drug Development and Clinical Practice 1 (3): 165–74. doi:10.2165/00129785-200101030-00002. PMID 12083965. 
  • Thibonnier M, Coles P, Thibonnier A, Shoham M (2002). "Molecular pharmacology and modeling of vasopressin receptors". Progress in Brain Research 139: 179–96. doi:10.1016/S0079-6123(02)39016-2. PMID 12436935. 
  • Ge D, Huang J, He J, Li B, Duan X, Chen R et al. (Jan 2005). "beta2-Adrenergic receptor gene variations associated with stage-2 hypertension in northern Han Chinese". Annals of Human Genetics 69 (Pt 1): 36–44. doi:10.1046/j.1529-8817.2003.00093.x. PMID 15638826. 
  • Muszkat M (Aug 2007). "Interethnic differences in drug response: the contribution of genetic variability in beta adrenergic receptor and cytochrome P4502C9". Clinical Pharmacology and Therapeutics 82 (2): 215–8. doi:10.1038/sj.clpt.6100142. PMID 17329986. 
  • Bucens D, Pain MC (Nov 1975). "Influence of hematocrit, blood gas tensions, and pH on pressure-flow relations in the isolated canine lung". Circulation Research 37 (5): 588–96. doi:10.1161/01.res.37.5.588. PMID 154.  Check date values in: |year= / |date= mismatch (help)
  • von Zastrow M, Kobilka BK (Feb 1992). "Ligand-regulated internalization and recycling of human beta 2-adrenergic receptors between the plasma membrane and endosomes containing transferrin receptors". The Journal of Biological Chemistry 267 (5): 3530–8. PMID 1371121. 
  • Gope R, Gope ML, Thorson A, Christensen M, Smyrk T, Chun M et al. (1992). "Genetic changes at the beta-2-adrenergic receptor locus on chromosome 5 in human colorectal carcinomas". Anticancer Research 11 (6): 2047–50. PMID 1663718. 
  • Bouvier M, Guilbault N, Bonin H (Feb 1991). "Phorbol-ester-induced phosphorylation of the beta 2-adrenergic receptor decreases its coupling to Gs". FEBS Letters 279 (2): 243–8. doi:10.1016/0014-5793(91)80159-Z. PMID 1848190. 
  • Yang-Feng TL, Xue FY, Zhong WW, Cotecchia S, Frielle T, Caron MG et al. (Feb 1990). "Chromosomal organization of adrenergic receptor genes". Proceedings of the National Academy of Sciences of the United States of America 87 (4): 1516–20. Bibcode:1990PNAS...87.1516Y. doi:10.1073/pnas.87.4.1516. PMC 53506. PMID 2154750. 
  • Hui KK, Yu JL (May 1989). "Effects of protein kinase inhibitor, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, on beta-2 adrenergic receptor activation and desensitization in intact human lymphocytes". The Journal of Pharmacology and Experimental Therapeutics 249 (2): 492–8. PMID 2470898. 
  • Hen R, Axel R, Obici S (Jun 1989). "Activation of the beta 2-adrenergic receptor promotes growth and differentiation in thyroid cells". Proceedings of the National Academy of Sciences of the United States of America 86 (12): 4785–8. Bibcode:1989PNAS...86.4785H. doi:10.1073/pnas.86.12.4785. PMC 287358. PMID 2471981. 
  • O'Dowd BF, Hnatowich M, Caron MG, Lefkowitz RJ, Bouvier M (May 1989). "Palmitoylation of the human beta 2-adrenergic receptor. Mutation of Cys341 in the carboxyl tail leads to an uncoupled nonpalmitoylated form of the receptor". The Journal of Biological Chemistry 264 (13): 7564–9. PMID 2540197. 
  • Bristow MR, Hershberger RE, Port JD, Minobe W, Rasmussen R (Mar 1989). "Beta 1- and beta 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium". Molecular Pharmacology 35 (3): 295–303. PMID 2564629. 
  • Emorine LJ, Marullo S, Delavier-Klutchko C, Kaveri SV, Durieu-Trautmann O, Strosberg AD (Oct 1987). "Structure of the gene for human beta 2-adrenergic receptor: expression and promoter characterization". Proceedings of the National Academy of Sciences of the United States of America 84 (20): 6995–9. Bibcode:1987PNAS...84.6995E. doi:10.1073/pnas.84.20.6995. PMC 299215. PMID 2823249. 
  • Chung FZ, Wang CD, Potter PC, Venter JC, Fraser CM (Mar 1988). "Site-directed mutagenesis and continuous expression of human beta-adrenergic receptors. Identification of a conserved aspartate residue involved in agonist binding and receptor activation". The Journal of Biological Chemistry 263 (9): 4052–5. PMID 2831218. 
  • Yang SD, Fong YL, Benovic JL, Sibley DR, Caron MG, Lefkowitz RJ (Jun 1988). "Dephosphorylation of the beta 2-adrenergic receptor and rhodopsin by latent phosphatase 2". The Journal of Biological Chemistry 263 (18): 8856–8. PMID 2837466. 
  • Kobilka BK, Dixon RA, Frielle T, Dohlman HG, Bolanowski MA, Sigal IS et al. (Jan 1987). "cDNA for the human beta 2-adrenergic receptor: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor". Proceedings of the National Academy of Sciences of the United States of America 84 (1): 46–50. Bibcode:1987PNAS...84...46K. doi:10.1073/pnas.84.1.46. PMC 304138. PMID 3025863. 
  • Chung FZ, Lentes KU, Gocayne J, Fitzgerald M, Robinson D, Kerlavage AR et al. (Jan 1987). "Cloning and sequence analysis of the human brain beta-adrenergic receptor. Evolutionary relationship to rodent and avian beta-receptors and porcine muscarinic receptors". FEBS Letters 211 (2): 200–6. doi:10.1016/0014-5793(87)81436-9. PMID 3026848. 

External links[edit]

  • 2-adrenoceptor". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.