Beta-2 adrenergic receptor

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Adrenoceptor beta 2, surface
2RH1.png
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).[1][2]
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols ADRB2 ; ADRB2R; ADRBR; B2AR; BAR; BETA2AR
External IDs OMIM109690 MGI87938 HomoloGene30948 IUPHAR: β2-adrenoceptor ChEMBL: 210 GeneCards: ADRB2 Gene
RNA expression pattern
PBB GE ADRB2 206170 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 154 11555
Ensembl ENSG00000169252 ENSMUSG00000045730
UniProt P07550 P18762
RefSeq (mRNA) NM_000024 NM_007420
RefSeq (protein) NP_000015 NP_031446
Location (UCSC) Chr 5:
148.21 – 148.21 Mb
Chr 18:
62.18 – 62.18 Mb
PubMed search [1] [2]

The beta-2 adrenergic receptor2 adrenoreceptor), also known as ADRB2, is a beta-adrenergic receptor within a cell membrane which reacts with adrenaline (epinephrine) as a hormone or neurotransmitter affecting muscles or organs. Also, ADRB2 denotes the human gene encoding it.[3]


Gene[edit]

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.[4]

Structure[edit]

The 3D crystallographic structure (see figure and links to the right) of the β2-adrenergic receptor has been determined[5][1][2] by making a fusion protein with lysozyme to increase the hydrophillic surface area of the protein for crystal contacts.

Mechanism[edit]

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.[6]

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.[7] This appears to be mediated by cAMP induced PKA phosphorylation of the receptor.[8]

Function[edit]

Actions of the β2 receptor include:

Muscular system[edit]

Tissue/Effect Function

Smooth muscle relaxation in:

uterus

inhibits labor
GI tract (decreases motility) Delay digestion during fight-or-flight response Insulin secretion from pancreas, leading to overall lower levels of blood glucose

detrusor urinae muscle of bladder wall[9] This effect is stronger than the alpha-1 receptor effect of contraction.

Delay need of micturition
seminal tract[10]
bronchi[11] Facilitate respiration (agonists can be useful in treating asthma)
Increase perfusion of target organs needed during fight-or-flight
striated muscle Tremor[10] (via PKA mediated facilitation of presynaptic Ca2+ influx leading to acetylcholine release)
Increased mass and contraction speed[10] fight-or-flight
glycogenolysis[10] provide glucose fuel

Circulatory system[edit]

Eye[edit]

In the normal eye, beta-2 stimulation by salbutamol increases intraocular pressure via net:

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[edit]

Other[edit]

Agonists[edit]

Antagonists[edit]

(Beta blockers)

* denotes selective agonists to the receptor.

See also[edit]

Interactions[edit]

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

References[edit]

  1. ^ a b PDB 2RH1; 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 ?2-adrenergic G protein-coupled receptor". Science 318 (5854): 1258–65. doi:10.1126/science.1150577. PMC 2583103. PMID 17962520. 
  2. ^ a b 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. doi:10.1126/science.1150609. PMID 17962519. 
  3. ^ "Entrez Gene: ADRB1 adrenergic, beta-1-, receptor". 
  4. ^ "Entrez Gene: ADRB2 adrenergic, beta-2-, receptor, surface". 
  5. ^ 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 (2007). "Crystal structure of the human β2-adrenergic G-protein-coupled receptor". Nature 450 (7168): 383–7. Bibcode:2007Natur.450..383R. doi:10.1038/nature06325. PMID 17952055. 
  6. ^ Rubenstein LA, Zauhar RJ, Lanzara RG (2006). "Molecular dynamics of a biophysical model for β2-adrenergic and G protein-coupled receptor activation". J. Mol. Graph. Model. 25 (4): 396–409. doi:10.1016/j.jmgm.2006.02.008. PMID 16574446. 
  7. ^ Chen-Izu Y, Xiao RP, Izu LT, Cheng H, Kuschel M, Spurgeon H, Lakatta EG (November 2000). "G(i)-dependent localization of beta(2)-adrenergic receptor signaling to L-type Ca(2+) channels". Biophys. J. 79 (5): 2547–56. Bibcode:2000BpJ....79.2547C. doi:10.1016/S0006-3495(00)76495-2. PMC 1301137. PMID 11053129. 
  8. ^ Zamah AM, Delahunty M, Luttrell LM, Lefkowitz RJ (August 2002). "Protein kinase A-mediated phosphorylation of the beta 2-adrenergic receptor regulates its coupling to Gs and Gi. Demonstration in a reconstituted system". J. Biol. Chem. 277 (34): 31249–56. doi:10.1074/jbc.M202753200. PMID 12063255. 
  9. ^ 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". Neurourol. Urodyn. 14 (2): 153–68. doi:10.1002/nau.1930140208. PMID 7540086. 
  10. ^ a b c d e Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4.  Page 163
  11. ^ a b c d e f Fitzpatrick, David; Purves, Dale; Augustine, George (2004). "Table 20:2". Neuroscience (Third ed.). Sunderland, Mass: Sinauer. ISBN 0-87893-725-0. 
  12. ^ Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4.  Page 270
  13. ^ Elenkov, I. J., R. L. Wilder, et al. (2000). "The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system.". Pharmacol Rev 52 (4): 595–638. PMID 11121511. 
  14. ^ 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". J. Biol. Chem. 276 (26): 24005–14. doi:10.1074/jbc.M011199200. PMID 11309381. 
  15. ^ 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". J. Biol. Chem. 274 (3): 1588–95. doi:10.1074/jbc.274.3.1588. PMID 9880537. 
  16. ^ 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". J. Biol. Chem. 276 (17): 14092–9. doi:10.1074/jbc.M008902200. PMID 11278447. 
  17. ^ 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". J. Biol. Chem. 273 (49): 33035–41. doi:10.1074/jbc.273.49.33035. PMID 9830057. 
  18. ^ Temkin P, Lauffer B, Jäger S, Cimermancic P, Krogan NJ, von Zastrow M (June 2011). "SNX27 mediates retromer tubule entry and endosome-to-plasma membrane trafficking of signalling receptors". Nat. Cell Biol. 13 (6): 715–21. doi:10.1038/ncb2252. PMC 3113693. PMID 21602791. 
  19. ^ 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". J. Biol. Chem. 277 (21): 18973–8. doi:10.1074/jbc.M201507200. PMID 11882663. 
  20. ^ 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". Proc. Natl. Acad. Sci. U.S.A. 95 (15): 8496–501. doi:10.1073/pnas.95.15.8496. PMC 21104. PMID 9671706. 
  21. ^ 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. doi:10.1038/33458. PMID 9560162. 

External links[edit]

  • 2-adrenoceptor". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. 

Further reading[edit]