Beta-2 adrenergic receptor
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, increased cAMP, and downstream L-type calcium channel interaction, mediates physiologic responses such as smooth muscle relaxation and bronchodilation.[5]
The official symbol for the human gene encoding the β2 adrenoreceptor is ADRB2.[6]
Gene
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.[7]
Structure
The 3D crystallographic structure (see figure and links to the right) of the β2-adrenergic receptor has been determined[8][9][10] 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.[11]
Mechanism
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 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.[12]
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.[13] This appears to be mediated by cAMP induced PKA phosphorylation of the receptor.[14]
Function
Muscular system
The β2 adrenoreceptor has been correlated with anabolic properties and muscular hypertrophy with usage of agents such as oral clenbuterol as well as intravenous albuterol, though oral albuterol did not generate the same impacts on muscle mass, suggesting that drugs with a short half-life do not maintain sufficient activation to achieve these effects.[15][16] Long-acting β2 agonists such as clenbuterol (not used clinically in the United States) are frequently abused performance-enhancing drugs for their anabolic, lipolytic, and performance-enhancing effects.[17] As a result, most of these agents are banned by WADA (World Anti-Doping Agency), though some are permissible under a therapeutic use exemption and are typically monitored for usage in athletes. Clenbuterol remains banned not as a beta-agonist, but rather an anabolic agent.
| Function | Tissue | Biological Role |
|---|---|---|
| Smooth muscle relaxation in: | GI tract (decreases motility) | Inhibition of digestion |
| Bronchi[18] | Facilitation of respiration. Hence, beta-2 agonists can be useful in treating asthma. | |
| Detrusor urinae muscle of bladder wall[19][20] This effect is stronger than the alpha-1 receptor effect of contraction. | Inhibition of need for micturition | |
| Uterus | Inhibition of labor | |
| Seminal tract[21] | ||
| Increased perfusion and vasodilation | Blood vessels and arteries to skeletal muscle including the smaller coronary arteries[22] and hepatic artery | Facilitation of muscle contraction and motility |
| Increased mass and contraction speed | Striated muscle[21] | |
| Insulin and glucagon secretion | Pancreas[23] | Increased blood glucose and uptake by skeletal muscle |
| Glycogenolysis[21] | ||
| Tremor | Motor nerve terminals.[21] Tremor is mediated by PKA mediated facilitation of presynaptic Ca2+ influx leading to acetylcholine release. | |
| Legend |
Circulatory system
- Heart muscle contraction
- Increase cardiac output (minor degree compared to β1).
- Increases heart rate [18] in sinoatrial node (SA node) (chronotropic effect).
- Increases atrial cardiac muscle contractility. (inotropic effect).
- Increases contractility and automaticity[18] of ventricular cardiac muscle.
- Dilate hepatic artery.
- Dilate arterioles to skeletal muscle.
Eye
In the normal eye, beta-2 stimulation by salbutamol increases intraocular pressure via net:
- Increase in production of aqueous humour by the ciliary process,
- Subsequent increased pressure-dependent uveoscleral outflow of humour, despite reduced drainage of humour via the Canal of Schlemm.
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
- Glycogenolysis and gluconeogenesis in liver.[18]
- Glycogenolysis and lactate release in skeletal muscle.[18]
- Contract sphincters of Gastrointestinal tract.
- Thickened secretions from salivary glands.[18]
- Insulin and glucagon secretion from pancreas.[23]
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 [24]
Ligands
Agonists
| Beta-2 adrenergic receptor | |
|---|---|
| Transduction mechanisms | Primary: Gs Secondary: Gi/o |
| Primary endogenous agonists | epinephrine, norepinephrine |
| Agonists | isoprenaline, salbutamol, salmeterol, others |
| Antagonists | carvedilol, propranolol, labetalol, others |
| Inverse agonists | N/A |
| Positive allosteric modulators | Zn2+ (low concentrations) |
| Negative allosteric modulators | Zn2+ (high concentrations) |
| External resources | |
| IUPHAR/BPS | 29 |
| DrugBank | P07550 |
| HMDB | HMDBP01634 |
Spasmolytics used in asthma and COPD
- Short-acting β2 agonists (SABA)
- bitolterol
- fenoterol
- hexoprenaline
- isoprenaline (INN) or isoproterenol (USAN)
- levosalbutamol (INN) or levalbuterol (USAN)
- orciprenaline (INN) or metaproterenol (USAN)
- pirbuterol
- procaterol
- salbutamol (INN) or albuterol (USAN)
- terbutaline
- Long-acting β2 agonists (LABA)
- arformoterol (some consider it to be an ultra-LABA)[25]
- bambuterol
- clenbuterol
- formoterol
- salmeterol
- Ultra-long-acting β2 agonists (ultra-LABA)
- carmoterol
- indacaterol
- milveterol (GSK 159797)
- olodaterol
- vilanterol (GSK 642444)
Tocolytic agents
- Short-acting β2 agonists (SABA)
- fenoterol
- hexoprenaline
- isoxsuprine
- ritodrine
- salbutamol (INN) or albuterol (USAN)
- terbutaline
β2 agonists used for other purposes
Antagonists
* denotes selective antagonist to the receptor.
Allosteric modulators
- compound-6FA,[26] PAM at intracellular binding site
Interactions
Beta-2 adrenergic receptor has been shown to interact with:
See also
References
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- GRCm38: Ensembl release 89: ENSMUSG00000045730 - Ensembl, May 2017
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- 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.
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- Liu, X.; Masoudi, A.; Kahsai, A. W.; Huang, L. Y.; Pani, B.; Staus, D. P.; Shim, P. J.; Hirata, K.; Simhal, R. K.; Schwalb, A. M.; Rambarat, P. K.; Ahn, S.; Lefkowitz, R. J.; Kobilka, B. (2019). "Mechanism of β2AR regulation by an intracellular positive allosteric modulator". Science. 364 (6447): 1283–1287. Bibcode:2019Sci...364.1283L. doi:10.1126/science.aaw8981. PMC 6705129. PMID 31249059.
- 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.
- 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.
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Further reading
- 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). Molecular pharmacology and modeling of vasopressin receptors. Progress in Brain Research. 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. 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.
- 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. S2CID 28959833.
- Yang-Feng TL, Xue FY, Zhong WW, Cotecchia S, Frielle T, Caron MG, Lefkowitz RJ, Francke U (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, Yang-Feng TL, Francke U, Caron MG, Lefkowitz RJ (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, Fraser CM, Venter JC (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. S2CID 221452296.
External links
- "β2-adrenoceptor". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
- Human ADRB2 genome location and ADRB2 gene details page in the UCSC Genome Browser.
- Overview of all the structural information available in the PDB for UniProt: P07550 ( Beta-2 adrenergic receptor) at the PDBe-KB.
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