The beta-2 adrenergic receptor (β2 adrenoreceptor), also known as ADRB2, is a cell membrane-spanning beta-adrenergic receptor that binds epinephrine (adrenaline), a hormone and neurotransmitter whose signaling, via adenylate cyclase stimulation through trimeric Gs proteins, increases cAMP, and, via downstream L-type calcium channel interaction, mediates physiologic responses such as smooth muscle relaxation and bronchodilation.[5]
Quick Facts ADRB2, Available structures ...
ADRB2 |
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Available structures |
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PDB | Ortholog search: PDBe RCSB |
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List of PDB id codes |
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4QKX, 2R4R, 2R4S, 2RH1, 3D4S, 3KJ6, 3NY8, 3NY9, 3NYA, 3P0G, 3PDS, 3SN6, 4GBR, 4LDE, 4LDL, 4LDO, 5D5A, 5D5B, 5JQH |
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Identifiers |
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Aliases | ADRB2, ADRB2R, ADRBR, B2AR, BAR, BETA2AR, adrenoceptor beta 2 |
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External IDs | OMIM: 109690; MGI: 87938; HomoloGene: 30948; GeneCards: ADRB2; OMA:ADRB2 - orthologs |
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Wikidata |
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Robert J. Lefkowitz[6] and Brian Kobilka[7] studied beta 2 adrenergic receptor as a model system which rewarded them the 2012 Nobel Prize in Chemistry[8] “for groundbreaking discoveries that reveal the inner workings of an important family of such receptors: G-protein-coupled-receptors”.
The official symbol for the human gene encoding the β2 adrenoreceptor is ADRB2.[9]
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.[10]
The 3D crystallographic structure (see figure and links to the right) of the β2-adrenergic receptor has been determined[11][12][13] by making a fusion protein with lysozyme to increase the hydrophilic surface area of the protein for crystal contacts. An alternative method, involving production of a fusion protein with an agonist, supported lipid-bilayer co-crystallization and generation of a 3.5 Å resolution structure.[14]
The crystal structure of the β2Adrenergic Receptor-Gs protein complex was solved in 2011. The largest conformational changes in the β2AR include a 14 Å outward movement at the cytoplasmic end of transmembrane segment 6 (TM6) and an alpha helical extension of the cytoplasmic end of TM5.[15]
This receptor is directly associated with one of its ultimate effectors, the class C L-type calcium channel CaV1.2.[citation needed] 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 counterbalancing phosphatase PP2A. Protein kinase A then goes on to phosphorylate (and thus inactivate) myosin light-chain kinase, which causes smooth muscle relaxation, accounting for the vasodilatory effects of beta 2 stimulation. 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.[16]
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.[17] This appears to be mediated by cAMP induced PKA phosphorylation of the receptor.[18]
Interestingly, Beta-2 adrenergic receptor was observed to localize exclusively to the T-tubular network of adult cardiomyocytes, as opposed to Beta-1 adrenergic receptor, which is observed also on the outer plasma membrane of the cell [19]
More information Function, Tissue ...
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Musculoskeletal system
Activation of the β2 adrenoreceptor with long-acting agents such as oral clenbuterol and intravenously-infused albuterol results in skeletomuscular hypertrophy and anabolism.[26][27] The comprehensive anabolic, lipolytic, and ergogenic effects of long-acting β2 agonists such as clenbuterol render them frequent targets as performance-enhancing drugs in athletes.[28] Consequently, such agents are monitored for and generally banned by WADA (World Anti-Doping Agency) with limited permissible usage under therapeutic exemptions; clenbuterol and other β2 adrenergic agents remain banned not as a beta-agonist, but rather an anabolic agent. These effects are largely attractive within agricultural contexts insofar that β2 adrenergic agents have seen notable extra-label usage in food-producing animals and livestock. While many countries including the United States have prohibited extra-label usage in food-producing livestock, the practice is still observed in many countries. [29][30]
Eye
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.
Other
- Inhibit histamine-release from mast cells.
- Increase protein content of secretions from lacrimal glands.
- Receptor also present in cerebellum.
- Bronchiole dilation (targeted while treating asthma attacks)
- Involved in brain - immune - communication [31]
Agonists
Quick Facts Transduction mechanisms, Primary endogenous agonists ...
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Spasmolytics used in asthma and COPD
- Short-acting β2 agonists (SABA)
- Long-acting β2 agonists (LABA)
- Ultra-long-acting β2 agonists (ultra-LABA)
- Short-acting β2 agonists (SABA)
β2 agonists used for other purposes
Antagonists
(Beta blockers)
* denotes selective antagonist to the receptor.
Allosteric modulators
- compound-6FA,[33] PAM at intracellular binding site
- Cellular swelling [34]
Beta-2 adrenergic receptor has been shown to interact with:
Johnson M (January 2006). "Molecular mechanisms of beta(2)-adrenergic receptor function, response, and regulation". The Journal of Allergy and Clinical Immunology. 117 (1): 18–24, quiz 25. doi:10.1016/j.jaci.2005.11.012. PMID 16387578.
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 β2-adrenergic G protein-coupled receptor". Science. 318 (5854): 1258–65. Bibcode:2007Sci...318.1258C. doi:10.1126/science.1150577. PMC 2583103. PMID 17962520.
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 β2-adrenergic receptor function". Science. 318 (5854): 1266–73. Bibcode:2007Sci...318.1266R. doi:10.1126/science.1150609. PMID 17962519. S2CID 1559802.
Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK (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. S2CID 4407117.
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.
Fitzpatrick D, Purves D, Augustine G (2004). "Table 20:2". Neuroscience (Third ed.). Sunderland, Mass: Sinauer. ISBN 978-0-87893-725-7.
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. S2CID 31114890.
Choo JJ, Horan MA, Little RA, Rothwell NJ (July 1992). "Anabolic effects of clenbuterol on skeletal muscle are mediated by beta 2-adrenoceptor activation". The American Journal of Physiology. 263 (1 Pt 1): E50-6. doi:10.1152/ajpendo.1992.263.1.E50. PMID 1322047.
Kamalakkannan G, Petrilli CM, George I, LaManca J, McLaughlin BT, Shane E, et al. (April 2008). "Clenbuterol increases lean muscle mass but not endurance in patients with chronic heart failure". The Journal of Heart and Lung Transplantation. 27 (4): 457–61. doi:10.1016/j.healun.2008.01.013. PMID 18374884.
"Clenbuterol" (PDF). Drug and Chemical Evaluation Section. Drug Enforcement Agency. Retrieved 15 November 2021.
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.
Sirbu A, Bathe-Peters M, Kumar J, Inoue A, Lohse MJ, Annibale P (August 2024). "Cell swelling enhances ligand-driven β-adrenergic signaling". Nature Communications. 15 (1): 1–12. doi:10.1038/s41467-024-52191-y.
Hall RA, Premont RT, Chow CW, Blitzer JT, Pitcher JA, Claing A, Stoffel RH, Barak LS, Shenolikar S, Weinman EJ, Grinstein S, Lefkowitz RJ (Apr 1998). "The beta2-adrenergic receptor interacts with the Na+/H+-exchanger regulatory factor to control Na+/H+ exchange". Nature. 392 (6676): 626–30. Bibcode:1998Natur.392..626H. doi:10.1038/33458. PMID 9560162. S2CID 4422540.
- 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. doi:10.1093/clinchem/35.5.721. 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. 1 (3): 165–74. doi:10.2165/00129785-200101030-00002. PMID 12083965. S2CID 116089602.
- Thibonnier M, Coles P, Thibonnier A, Shoham M (2002). "Chapter 14 Molecular pharmacology and modeling of vasopressin receptors". Vasopressin and Oxytocin: From Genes to Clinical Applications. Progress in Brain Research. Vol. 139. pp. 179–96. doi:10.1016/S0079-6123(02)39016-2. ISBN 9780444509826. PMID 12436935.
- Ge D, Huang J, He J, Li B, Duan X, Chen R, Gu D (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. S2CID 6485276.
- 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. S2CID 10381767.
- 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. doi:10.1016/S0021-9258(19)50762-1. PMID 1371121.
- Gope R, Gope ML, Thorson A, Christensen M, Smyrk T, Chun M, Alvarez L, Wildrick DM, Boman BM (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.
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