Beta-2 adrenergic receptor
|Adrenoceptor beta 2, surface|
Crystallographic structure of the ?2-adrenergic receptor depicted as a green cartoon and the bound partial inverse agonist carazolol ligand as spheres (carbon atom = grey, oxygen = red, nitrogen = blue). The phospholipid bilayer is depicted as blue spheres (phosphate head groups) and yellow lines (lipid sidechains).
|Symbols||; ADRB2R; ADRBR; B2AR; BAR; BETA2AR|
|External IDs||IUPHAR: ChEMBL: GeneCards:|
|RNA expression pattern|
The beta-2 adrenergic receptor (β2 adrenoreceptor), also known as ADRB2, is a cell membrane-spanning beta-adrenergic receptor that interacts with (binds) epinephrine a hormone and neurotransmitter (ligand synonym, adrenaline) whose signaling, via a downstream L-type calcium channel interaction, mediates physiologic responses such as smooth muscle relaxation and bronchodilation.
The official symbol for the human gene encoding the β2 adrenoreceptor is ADRB2.
- Gene 1
- Structure 2
- Mechanism 3
- Muscular system 4.1
- Circulatory system 4.2
- Eye 4.3
- Digestive system 4.4
- Other 4.5
- Agonists 5
- Antagonists 6
- Interactions 7
- See also 8
- References 9
- Further reading 10
- External links 11
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.
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 Gs G protein, which activates adenylyl cyclase, catalysing the formation of cyclic adenosine monophosphate (cAMP) which then activates protein kinase A, and the counterbalancing phosphatase PP2A. 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.
Actions of the β2 receptor include:
Smooth muscle relaxation in:
|GI tract (decreases motility)||Delay digestion during fight-or-flight response|
|Delay need of micturition|
|bronchi||Facilitate respiration (agonists can be useful in treating asthma)|
|Increase perfusion of target organs||needed during fight-or-flight|
|striated muscle||Tremor (via PKA mediated facilitation of presynaptic Ca2+ influx leading to acetylcholine release)|
|Increased mass and contraction speed||fight-or-flight|
|glycogenolysis||provide glucose fuel|
|pancreas||Insulin secretion||increases uptake of glucose by muscle|
- Heart muscle contraction
- Increase cardiac output (minor degree compared to β1).
- Dilate hepatic artery.
- Dilate arterioles to skeletal muscle.
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.
- Glycogenolysis and gluconeogenesis in liver.
- Glycogenolysis and lactate release in skeletal muscle.
- Contract sphincters of GI tract.
- Thickened secretions from salivary glands.
- Insulin secretion from pancreas
- Inhibit histamine-release from mast cells.
- Increase protein content of secretions from lacrimal glands.
- Increase renin secretion from kidney.
- Receptor also present in cerebellum.
- Bronchiole dilation (targeted while treating asthma attacks)
- Involved in brain - immune - communication 
- Short acting beta agonist (SABA)
- Ultra long lasting beta agonist (LABA)
* denotes selective agonists to the receptor.
Beta-2 adrenergic receptor has been shown to interact with:
- Other adrenergic receptors
- Discovery and development of beta2 agonists
- ; Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC (2007). -adrenergic G protein-coupled receptor"2"High-resolution crystal structure of an engineered human ?. Science 318 (5854): 1258–65.
- 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 ?2-adrenergic receptor function". Science 318 (5854): 1266–73.
- "Entrez Gene: ADRB2 adrenoceptor beta 2, surface". Retrieved 8 February 2015.
- "Entrez Gene: ADRB2 adrenergic, beta-2-, receptor, surface".
- 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 (Nov 2007). "Crystal structure of the human beta2 adrenergic G-protein-coupled receptor". Nature 450 (7168): 383–7.
- 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.
- Chen-Izu Y, Xiao RP, Izu LT, Cheng H, Kuschel M, Spurgeon H, Lakatta EG (Nov 2000). "G(i)-dependent localization of beta(2)-adrenergic receptor signaling to L-type Ca(2+) channels". Biophysical Journal 79 (5): 2547–56.
- 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.
- 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.
- Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. Page 163
- Fitzpatrick, David; Purves, Dale; Augustine, George (2004). "Table 20:2". Neuroscience (Third ed.). Sunderland, Mass: Sinauer.
- Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. p. 270.
- 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.
- 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.
- 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.
- 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.
- 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.
- Temkin P, Lauffer B, Jäger S, Cimermancic P, Krogan NJ, von Zastrow M (Jun 2011). "SNX27 mediates retromer tubule entry and endosome-to-plasma membrane trafficking of signalling receptors". Nature Cell Biology 13 (6): 715–21.
- 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.
- Hall RA, Ostedgaard LS, Premont RT, Blitzer JT, Rahman N, Welsh MJ, Lefkowitz RJ (Jul 1998). "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.
- Hall RA, Premont RT, Chow CW, Blitzer JT, Pitcher JA, Claing A, Stoffel RH, Barak LS, Shenolikar S, Weinman EJ, Grinstein S, Lefkowitz RJ (Apr 1998). "The beta2-adrenergic receptor interacts with the Na+/H+-exchanger regulatory factor to control Na+/H+ exchange". Nature 392 (6676): 626–30.
- 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.
- Taylor DR, Kennedy MA (2002). "Genetic variation of the beta(2)-adrenoceptor: its functional and clinical importance in bronchial asthma". American Journal of Pharmacogenomics : Genomics-Related Research in Drug Development and Clinical Practice 1 (3): 165–74.
- Thibonnier M, Coles P, Thibonnier A, Shoham M (2002). "Molecular pharmacology and modeling of vasopressin receptors". Progress in Brain Research 139: 179–96.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- -adrenoceptor"2"β. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.