Thành viên:Naazulene/Thụ thể beta-2 adrenergic
Thụ thể beta-2 adrenergic (β2 adrenoreceptor), còn được viết tắt là ADRB2, là
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 earned 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
[sửa | sửa mã nguồn]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]
Cấu trúc
[sửa | sửa mã nguồn]Cấu trúc tinh thể 3D của thụ thể này đã được xác định bằng cách tạo protein dung hợp với lysosome để làm tăng diện tích bề mặt kỵ nước của protein.
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
[sửa | sửa mã nguồn]This receptor is directly associated with one of its ultimate effectors, the class C L-type calcium channel CaV1.2.[cần dẫn nguồn] 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
[sửa | sửa mã nguồn]| Chức năng | Tissue | Biological Role |
|---|---|---|
| Giãn cơ | 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
[sửa | sửa mã nguồn]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
[sửa | sửa mã nguồn]- Heart muscle contraction
- Increase cardiac output (minor degree compared to β1).
- Increases heart rate[16] in sinoatrial node (SA node) (chronotropic effect).
- Increases atrial cardiac muscle contractility. (inotropic effect).
- Increases contractility and automaticity[16] of ventricular cardiac muscle.
- Dilate hepatic artery.
- Dilate arterioles to skeletal muscle.
Eye
[sửa | sửa mã nguồn]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
[sửa | sửa mã nguồn]- Glycogenolysis and gluconeogenesis in liver.[16]
- Glycogenolysis and lactate release in skeletal muscle.[16]
- Contract sphincters of Gastrointestinal tract.
- Thickened secretions from salivary glands.[16]
- Insulin and glucagon secretion from pancreas.[21]
Other
[sửa | sửa mã nguồn]- 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
[sửa | sửa mã nguồn]Agonists
[sửa | sửa mã nguồn]Spasmolytics used in asthma and COPD
[sửa | sửa mã nguồn]- 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)[28]
- bambuterol
- clenbuterol
- formoterol
- salmeterol
- Ultra-long-acting β2 agonists (ultra-LABA)
- carmoterol
- indacaterol
- milveterol (GSK 159797)
- olodaterol
- vilanterol (GSK 642444)
Tocolytic agents
[sửa | sửa mã nguồn]- Short-acting β2 agonists (SABA)
- fenoterol
- hexoprenaline
- isoxsuprine
- ritodrine
- salbutamol (INN) or albuterol (USAN)
- terbutaline
β2 agonists used for other purposes
[sửa | sửa mã nguồn]Antagonists
[sửa | sửa mã nguồn]* denotes selective antagonist to the receptor.
Allosteric modulators
[sửa | sửa mã nguồn]Interactions
[sửa | sửa mã nguồn]Beta-2 adrenergic receptor has been shown to interact with:
See also
[sửa | sửa mã nguồn]References
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- ^ “The Nobel Prize in Chemistry 2012”. NobelPrize.org (bằng tiếng Anh). Truy cập ngày 4 tháng 7 năm 2021.
- ^ “The Nobel Prize in Chemistry 2012”. NobelPrize.org (bằng tiếng Anh). Truy cập ngày 4 tháng 7 năm 2021.
- ^ “The Nobel Prize in Chemistry 2012”. NobelPrize.org (bằng tiếng Anh). Truy cập ngày 4 tháng 7 năm 2021.
- ^ “Entrez Gene: ADRB2 adrenoceptor beta 2, surface”. Truy cập ngày 8 tháng 2 năm 2015.
- ^ “Entrez Gene: ADRB2 adrenergic, beta-2-, receptor, surface”.
- ^ 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 (tháng 11 năm 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.
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Further reading
[sửa | sửa mã nguồn]- Frielle T, Caron MG, Lefkowitz RJ (tháng 5 năm 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. 139. tr. 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 (tháng 1 năm 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 (tháng 8 năm 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 (tháng 2 năm 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.
- Bouvier M, Guilbault N, Bonin H (tháng 2 năm 1991). “Phorbol-ester-induced phosphorylation of the beta 2-adrenergic receptor decreases its coupling to Gs”. FEBS Letters. 279 (2): 243–8. Bibcode:1991FEBSL.279..243B. 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 (tháng 2 năm 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 (tháng 5 năm 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 (tháng 6 năm 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 (tháng 5 năm 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. doi:10.1016/S0021-9258(18)83271-9. PMID 2540197.
- Bristow MR, Hershberger RE, Port JD, Minobe W, Rasmussen R (tháng 3 năm 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 (tháng 10 năm 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 (tháng 3 năm 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. doi:10.1016/S0021-9258(18)68888-X. PMID 2831218.
- Yang SD, Fong YL, Benovic JL, Sibley DR, Caron MG, Lefkowitz RJ (tháng 6 năm 1988). “Dephosphorylation of the beta 2-adrenergic receptor and rhodopsin by latent phosphatase 2”. The Journal of Biological Chemistry. 263 (18): 8856–8. doi:10.1016/S0021-9258(18)68386-3. PMID 2837466.
- Kobilka BK, Dixon RA, Frielle T, Dohlman HG, Bolanowski MA, Sigal IS, Yang-Feng TL, Francke U, Caron MG, Lefkowitz RJ (tháng 1 năm 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 (tháng 1 năm 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. Bibcode:1987FEBSL.211..200C. doi:10.1016/0014-5793(87)81436-9. PMID 3026848. S2CID 221452296.
External links
[sửa | sửa mã nguồn]- “β2-adrenoceptor”. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Bản gốc lưu trữ ngày 12 tháng 1 năm 2015. Truy cập ngày 25 tháng 11 năm 2008.
- Vị trí bộ gen ADRB2 ở người và thông tin chi tiết về gen ADRB2 có sẵn trên UCSC Genome Browser.
- Tổng quan về mọi thông tin cấu trúc có sẵn trên PDB cho UniProt: P07550 ( Beta-2 adrenergic receptor) tại PDBe-KB.