Biology:Beta-2 adrenergic receptor

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Short description: Mammalian protein found in humans

Template:Cs1 config

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1]

Robert J. Lefkowitz[2] and Brian Kobilka[3] studied beta 2 adrenergic receptor as a model system which rewarded them the 2012 Nobel Prize in Chemistry[4] “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.[5]

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.[6]

Structure

The 3D crystallographic structure (see figure and links to the right) of the β2-adrenergic receptor has been determined[7][8][9] 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.[10]

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.[11]

Mechanism

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.[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] 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 [15]

Function

Function Tissue Biological Role
Smooth muscle relaxation in: GI tract (decreases motility) Inhibition of digestion
Bronchi[16] Facilitation of respiration.
Detrusor urinae muscle of bladder wall[17][18] This effect is stronger than the alpha-1 receptor effect of contraction. Inhibition of need for micturition
Uterus Inhibition of labor
Seminal tract[19]
Increased perfusion and vasodilation Blood vessels and arteries to skeletal muscle including the smaller coronary arteries[20] and hepatic artery Facilitation of muscle contraction and motility
Increased mass and contraction speed Striated muscle[19]
Insulin and glucagon secretion Pancreas[21] Increased blood glucose and uptake by skeletal muscle
Glycogenolysis[19]
Tremor Motor nerve terminals.[19] Tremor is mediated by PKA mediated facilitation of presynaptic 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 clenbuterol and intravenously-infused albuterol results in skeletomuscular hypertrophy and anabolism.[22][23] 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.[24] 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. [25][26]

Circulatory system

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

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 [27]

Ligands

Agonists

Template:Infobox GPCR

Spasmolytics used in asthma and COPD

Tocolytic agents

β2 agonists used for other purposes

Antagonists

(Beta blockers)

* denotes selective antagonist to the receptor.

Allosteric modulators

  • compound-6FA,[29] PAM at intracellular binding site

Interactions

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


See also

References

  1. ↑ "Molecular mechanisms of beta(2)-adrenergic receptor function, response, and regulation". The Journal of Allergy and Clinical Immunology 117 (1): 18–24; quiz 25. January 2006. doi:10.1016/j.jaci.2005.11.012. PMID 16387578. 
  2. ↑ "The Nobel Prize in Chemistry 2012" (in en-US). https://www.nobelprize.org/prizes/chemistry/2012/lefkowitz/facts/. 
  3. ↑ "The Nobel Prize in Chemistry 2012" (in en-US). https://www.nobelprize.org/prizes/chemistry/2012/kobilka/facts/. 
  4. ↑ "The Nobel Prize in Chemistry 2012" (in en-US). https://www.nobelprize.org/prizes/chemistry/2012/summary/. 
  5. ↑ "Entrez Gene: ADRB2 adrenoceptor beta 2, surface". https://www.ncbi.nlm.nih.gov/gene/154. 
  6. ↑ "Entrez Gene: ADRB2 adrenergic, beta-2-, receptor, surface". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=154. 
  7. ↑ "High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor". Science 318 (5854): 1258–65. 2007. doi:10.1126/science.1150577. PMID 17962520. Bibcode: 2007Sci...318.1258C. 
  8. ↑ "GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function". Science 318 (5854): 1266–73. 2007. doi:10.1126/science.1150609. PMID 17962519. Bibcode: 2007Sci...318.1266R. 
  9. ↑ "Crystal structure of the human beta2 adrenergic G-protein-coupled receptor". Nature 450 (7168): 383–7. Nov 2007. doi:10.1038/nature06325. PMID 17952055. Bibcode: 2007Natur.450..383R. 
  10. ↑ "Dissecting the Structure of Membrane Proteins". Genetic Engineering & Biotechnology News 35 (17): 16. 1 October 2015. doi:10.1089/gen.35.07.09. http://www.genengnews.com/gen-articles/dissecting-the-structure-of-membrane-proteins/5583/. (Subscription content?)
  11. ↑ "Crystal structure of the β2 adrenergic receptor-Gs protein complex". Nature 477 (7366): 549–55. July 2011. doi:10.1038/nature10361. PMID 21772288. Bibcode: 2011Natur.477..549R. 
  12. ↑ "Molecular dynamics of a biophysical model for beta2-adrenergic and G protein-coupled receptor activation". Journal of Molecular Graphics & Modelling 25 (4): 396–409. Dec 2006. doi:10.1016/j.jmgm.2006.02.008. PMID 16574446. 
  13. ↑ "G(i)-dependent localization of beta(2)-adrenergic receptor signaling to L-type Ca(2+) channels". Biophysical Journal 79 (5): 2547–56. Nov 2000. doi:10.1016/S0006-3495(00)76495-2. PMID 11053129. Bibcode: 2000BpJ....79.2547C. 
  14. ↑ "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. Aug 2002. doi:10.1074/jbc.M202753200. PMID 12063255. 
  15. ↑ "Visualization of β-adrenergic receptor dynamics and differential localization in cardiomyocytes". Proceedings of the National Academy of Sciences of the United States of America 118 (23): e2101119118. June 2021. doi:10.1073/pnas.2101119118. ISSN 0027-8424. PMID 34088840. 
  16. ↑ 16.0 16.1 16.2 16.3 16.4 16.5 "Table 20:2". Neuroscience (Third ed.). Sunderland, Mass: Sinauer. 2004. ISBN 978-0-87893-725-7. 
  17. ↑ "Response of guinea pig smooth and striated urethral sphincter to cromakalim, prazosin, nifedipine, nitroprusside, and electrical stimulation". Neurourology and Urodynamics 14 (2): 153–68. 1995. doi:10.1002/nau.1930140208. PMID 7540086. 
  18. ↑ "Adrenoceptor function and expression in bladder urothelium and lamina propria". Urology 81 (1): 211.e1–7. January 2013. doi:10.1016/j.urology.2012.09.011. PMID 23200975. 
  19. ↑ 19.0 19.1 19.2 19.3 19.4 Pharmacology. Edinburgh: Churchill Livingstone. 2003. ISBN 978-0-443-07145-4.  Page 163
  20. ↑ Pharmacology. Edinburgh: Churchill Livingstone. 2003. p. 270. ISBN 978-0-443-07145-4. 
  21. ↑ 21.0 21.1 "beta-Agonists and metabolism". The Journal of Allergy and Clinical Immunology 110 (6 Suppl): S313-7. December 2002. doi:10.1067/mai.2002.129702. PMID 12464941. 
  22. ↑ "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. July 1992. doi:10.1152/ajpendo.1992.263.1.E50. PMID 1322047. 
  23. ↑ "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. April 2008. doi:10.1016/j.healun.2008.01.013. PMID 18374884. 
  24. ↑ "The rush to adrenaline: drugs in sport acting on the beta-adrenergic system". British Journal of Pharmacology 154 (3): 584–97. June 2008. doi:10.1038/bjp.2008.164. PMID 18500380. 
  25. ↑ "Clenbuterol". Drug Enforcement Agency. https://www.deadiversion.usdoj.gov/drug_chem_info/clenbuterol.pdf. 
  26. ↑ "Food and Drugs - ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS". U.S. Food and Drug Administration. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=530.41. 
  27. ↑ "The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system". Pharmacological Reviews 52 (4): 595–638. Dec 2000. PMID 11121511. 
  28. ↑ "ultra-long-acting beta2-adrenoceptor agonists: an emerging therapeutic option for asthma and COPD?". Drugs 67 (4): 503–15. 2007. doi:10.2165/00003495-200767040-00002. PMID 17352511. 
  29. ↑ "Mechanism of β2AR regulation by an intracellular positive allosteric modulator". Science 364 (6447): 1283–1287. June 2019. doi:10.1126/science.aaw8981. PMID 31249059. Bibcode: 2019Sci...364.1283L. 
  30. ↑ "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. Jun 2001. doi:10.1074/jbc.M011199200. PMID 11309381. 
  31. ↑ "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. Jan 1999. doi:10.1074/jbc.274.3.1588. PMID 9880537. 
  32. ↑ "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. Apr 2001. doi:10.1074/jbc.M008902200. PMID 11278447. 
  33. ↑ "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. Dec 1998. doi:10.1074/jbc.273.49.33035. PMID 9830057. 
  34. ↑ "SNX27 mediates retromer tubule entry and endosome-to-plasma membrane trafficking of signalling receptors". Nature Cell Biology 13 (6): 715–21. Jun 2011. doi:10.1038/ncb2252. PMID 21602791. 
  35. ↑ "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. May 2002. doi:10.1074/jbc.M201507200. PMID 11882663. 
  36. ↑ "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. Jul 1998. doi:10.1073/pnas.95.15.8496. PMID 9671706. Bibcode: 1998PNAS...95.8496H. 
  37. ↑ "The beta2-adrenergic receptor interacts with the Na+/H+-exchanger regulatory factor to control Na+/H+ exchange". Nature 392 (6676): 626–30. Apr 1998. doi:10.1038/33458. PMID 9560162. Bibcode: 1998Natur.392..626H. 

Further reading

External links



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