The 3D crystallographic structure (see figure and links to the right) of the β2-adrenergic receptor has been determined[11][12][13] by making afusion protein withlysozyme 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 CL-type calcium channel CaV1.2.[citation needed] This receptor-channel complex iscoupled to theGsG protein, which activatesadenylyl cyclase, catalysing the formation ofcyclic adenosine monophosphate (cAMP) which then activatesprotein kinase A, and counterbalancingphosphatasePP2A. 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 withGi, 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]
Activation of the β2 adrenoreceptor with long-acting agents such as oralclenbuterol and intravenously-infusedalbuterol 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]
Subsequent increased pressure-dependent uveoscleral outflow of humour,despite reduced drainage of humour via theCanal of Schlemm.
Inglaucoma, 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 astimolol may be employed.
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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.PMID1322047.
^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.PMID18374884.
^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.PMID11121511.
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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.PMID17329986.S2CID10381767.
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.PMID1663718.
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