Beta-2 adrenergic receptor
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RefSeq (protein) | |||||||||
Location (UCSC) | Chr 5: 148.83 – 148.83 Mb | Chr 18: 62.31 – 62.31 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
The beta-2 adrenergic receptor (β2 adrenoreceptor), also known as ADRB2, is a cell membrane-spanning
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]
Gene
The ADRB2 gene is
Structure
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]
Mechanism
This receptor is directly associated with one of its ultimate effectors, the class C
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]
Function
Function | Tissue | Biological Role |
---|---|---|
Smooth muscle relaxation in: | GI tract (decreases motility)
|
Inhibition of digestion |
Bronchi[20]
|
Facilitation of respiration. | |
alpha-1 receptor effect of contraction.
|
Inhibition of need for micturition
| |
Uterus | Inhibition of labor | |
Seminal tract[23] | ||
Increased perfusion and vasodilation | Facilitation of muscle contraction and motility | |
Increased mass and contraction speed | Striated muscle[23]
| |
Insulin and glucagon secretion | Pancreas[25] | Increased blood glucose and uptake by skeletal muscle |
Glycogenolysis[23] | ||
Tremor | Motor nerve terminals. Ca2+ influx leading to acetylcholine release.
|
Legend
The function facilitates the fight-or-flight response.
|
Musculoskeletal system
Activation of the β2 adrenoreceptor with long-acting agents such as oral
Circulatory system
- Heart muscle contraction
- Increase cardiac output (minor degree compared to β1).
- Increases heart rate[20] in sinoatrial node (SA node) (chronotropic effect).
- Increases inotropiceffect).
- Increases contractility and ventricularcardiac 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 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.[20]
- Glycogenolysis and lactate release in skeletal muscle.[20]
- Contract sphincters of Gastrointestinal tract.
- Thickened secretions from salivary glands.[20]
- Insulin and glucagon secretion from pancreas.[25]
Other
- Inhibit 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]
Ligands
Agonists
Beta-2 adrenergic receptor | |
---|---|
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
- INN) or isoproterenol (USAN)
- INN) or levalbuterol (USAN)
- INN) or metaproterenol (USAN)
- pirbuterol
- procaterol
- INN) or albuterol (USAN)
- terbutaline
- Long-acting β2 agonists (LABA)
- arformoterol (some consider it to be an ultra-LABA)[32]
- 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
- INN) or albuterol (USAN)
- terbutaline
β2 agonists used for other purposes
Antagonists
* denotes selective antagonist to the receptor.
Allosteric modulators
- compound-6FA,[33] PAM at intracellular binding site
Interactions
Beta-2 adrenergic receptor has been shown to
See also
- Other adrenergic receptors
- Discovery and development of beta2 agonists
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000169252 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000045730 - 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.
- PMID 16387578.
- ^ "The Nobel Prize in Chemistry 2012". NobelPrize.org. Retrieved 2021-07-04.
- ^ "The Nobel Prize in Chemistry 2012". NobelPrize.org. Retrieved 2021-07-04.
- ^ "The Nobel Prize in Chemistry 2012". NobelPrize.org. Retrieved 2021-07-04.
- ^ "Entrez Gene: ADRB2 adrenoceptor beta 2, surface". Retrieved 8 February 2015.
- ^ "Entrez Gene: ADRB2 adrenergic, beta-2-, receptor, surface".
- PMID 17962520.
- S2CID 1559802.
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- .(subscription required)
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- ^ ISBN 978-0-87893-725-7.
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- ^ ISBN 978-0-443-07145-4. Page 163
- ISBN 978-0-443-07145-4.
- ^ PMID 12464941.
- PMID 1322047.
- PMID 18374884.
- PMID 18500380.
- ^ "Clenbuterol" (PDF). Drug and Chemical Evaluation Section. Drug Enforcement Agency. Retrieved 15 November 2021.
- ^ "Food and Drugs - ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS". U.S. Food and Drug Administration. Retrieved 15 November 2021.
- PMID 11121511.
- S2CID 46976912.
- PMID 31249059.
- PMID 11309381.
- PMID 9880537.
- PMID 11278447.
- PMID 9830057.
- PMID 21602791.
- PMID 11882663.
- PMID 9671706.
- S2CID 4422540.
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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. S2CID 221452296.
External links
- "β2-adrenoceptor". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2015-01-12. Retrieved 2008-11-25.
- 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.