The 3D crystallographic structure (see figure and links to the right) of the β2-adrenergic receptor has been determined 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.
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 GsG protein, which activates adenylyl cyclase, catalysing the formation of cyclic adenosine monophosphate (cAMP) which then activates protein kinase A, and counterbalancing phosphatasePP2A. 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.
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. This appears to be mediated by cAMP induced PKA phosphorylation of the receptor.
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.
^Johnson M (January 2006). “Molecular mechanisms of beta(2)-adrenergic receptor function, response, and regulation”. The Journal of Allergy and Clinical Immunology. 117 (1): 18–24, quiz 25. doi:10.1016/j.jaci.2005.11.012. PMID16387578.
^Rubenstein LA, Zauhar RJ, Lanzara RG (Dec 2006). “Molecular dynamics of a biophysical model for beta2-adrenergic and G protein-coupled receptor activation”. Journal of Molecular Graphics & Modelling. 25 (4): 396–409. doi:10.1016/j.jmgm.2006.02.008. PMID16574446.
^Zamah AM, Delahunty M, Luttrell LM, Lefkowitz RJ (Aug 2002). “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. doi:10.1074/jbc.M202753200. PMID12063255.
^ abcdefFitzpatrick D, Purves D, Augustine G (2004). “Table 20:2”. Neuroscience (Third ed.). Sunderland, Mass: Sinauer. ISBN 0-87893-725-0.
^von Heyden B, Riemer RK, Nunes L, Brock GB, Lue TF, Tanagho EA (1995). “Response of guinea pig smooth and striated urethral sphincter to cromakalim, prazosin, nifedipine, nitroprusside, and electrical stimulation”. Neurourology and Urodynamics. 14 (2): 153–68. doi:10.1002/nau.1930140208. PMID7540086.
^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.
^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. PMID11309381.
^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. PMID9880537.
^McVey M, Ramsay D, Kellett E, Rees S, Wilson S, Pope AJ, Milligan G (Apr 2001). “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. doi:10.1074/jbc.M008902200. PMID11278447.
^Karoor V, Wang L, Wang HY, Malbon CC (Dec 1998). “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. doi:10.1074/jbc.273.49.33035. PMID9830057.
^Karthikeyan S, Leung T, Ladias JA (May 2002). “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. doi:10.1074/jbc.M201507200. PMID11882663.
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. PMID2541947.
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. PMID12083965.
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. PMID15638826.
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.
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. PMID1371121.
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.
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. PMID1848190.
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. PMID2470898.
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. PMID2540197.
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. PMID2564629.
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. PMID2831218.
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. PMID2837466.
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. PMID3026848.