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).^[1]^[2]

Available structures

PDB

Ortholog search: PDBe, RCSB

List of PDB id codes
1GQ4, 2R4R, 2R4S, 2RH1, 3D4S, 3KJ6, 3NY8, 3NY9, 3NYA, 3P0G, 3PDS, 3SN6, 4GBR, 4LDE, 4LDL, 4LDO, 4QKX

Identifiers

Symbols

ADRB2 ; ADRB2R; ADRBR; B2AR; BAR; BETA2AR

External IDs

OMIM: 109690 MGI: 87938 HomoloGene: 30948 IUPHAR: 29 ChEMBL: 210 GeneCards: ADRB2 Gene

Gene ontology
Molecular function	• G-protein alpha-subunit binding • beta2-adrenergic receptor activity • protein binding • drug binding • adenylate cyclase binding • potassium channel regulator activity • B2 bradykinin receptor binding • protein complex binding • dopamine binding • ionotropic glutamate receptor binding • protein homodimerization activity • epinephrine binding • norepinephrine binding
Cellular component	• nucleus • lysosome • endosome • plasma membrane • integral component of plasma membrane • apical plasma membrane • axon • neuronal cell body membrane • sarcolemma • dendritic spine • receptor complex
Biological process	• diet induced thermogenesis • vasodilation by norepinephrine-epinephrine involved in regulation of systemic arterial blood pressure • desensitization of G-protein coupled receptor protein signaling pathway by arrestin • diaphragm contraction • positive regulation of the force of heart contraction by epinephrine • receptor-mediated endocytosis • cell surface receptor signaling pathway • activation of transmembrane receptor protein tyrosine kinase activity • adenylate cyclase-modulating G-protein coupled receptor signaling pathway • activation of adenylate cyclase activity • cell-cell signaling • female pregnancy • aging • positive regulation of cell proliferation • associative learning • endosome to lysosome transport • response to cold • positive regulation of sodium ion transport • negative regulation of angiogenesis • negative regulation of ossification • positive regulation of bone mineralization • positive regulation of protein ubiquitination • heat generation • response to progesterone • positive regulation of ATPase activity • response to testosterone • synaptic transmission, glutamatergic • negative regulation of urine volume • negative regulation of multicellular organism growth • wound healing • positive regulation of apoptotic process • positive regulation of potassium ion transport • positive regulation of MAPK cascade • response to estrogen • estrous cycle • bone resorption • positive regulation of vasodilation • positive regulation of transcription from RNA polymerase II promoter • negative regulation of smooth muscle contraction • positive regulation of skeletal muscle tissue growth • negative regulation of inflammatory response • brown fat cell differentiation • regulation of calcium ion transport • regulation of sensory perception of pain • regulation of excitatory postsynaptic membrane potential • cellular response to hypoxia • response to dexamethasone • response to monoamine • adenylate cyclase-activating adrenergic receptor signaling pathway • negative regulation of platelet aggregation • liver regeneration • activation of mitophagy in response to mitochondrial depolarization
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

154

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 5:
148.83 – 148.83 Mb

Chr 18:
62.18 – 62.18 Mb

PubMed search

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. Unlike other adrenergic receptors, norepinephrine does not produce β₂ receptor stimulation.

The official symbol for the human gene encoding the β₂ adrenoreceptor is ADRB2.^[3]

Gene

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

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 hydrophilic surface area of the protein for crystal contacts.

Mechanism

This receptor is directly associated with one of its ultimate effectors, the class C L-type calcium channel Ca_V1.2. This receptor-channel complex is coupled to the G_s 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 G_i, possibly providing a mechanism by which response to ligand is highly localized within cells. In contrast, Beta-1 Adrenergic Receptors are coupled only to G_s, 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

Actions of the β₂ receptor include:

Muscular system

Tissue/Effect		Function
Smooth muscle relaxation in:	uterus	inhibits labor
	GI tract (decreases motility)	Delay digestion during fight-or-flight response
	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)
blood vessels dilates smaller coronary arteries,^[12] hepatic artery, arteries to skeletal muscle	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
pancreas	Insulin secretion	increases uptake of glucose by muscle

Circulatory system

Heart muscle contraction
Increase cardiac output (minor degree compared to β₁).
- Increase heart rate ^[11] in sinoatrial node (SA node) (chronotropic effect).
- Increase atrial cardiac muscle contractility. (inotropic effect).
- Increases contractility and automaticity^[11] of ventricular cardiac muscle.
Dilate hepatic artery.
Dilate arterioles to skeletal muscle.

Eye

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

Glycogenolysis and gluconeogenesis in liver.^[11]
Glycogenolysis and lactate release in skeletal muscle.^[11]
Contract sphincters of GI tract.
Thickened secretions from salivary glands.^[11]
Insulin secretion from pancreas

Other

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 ^[13]

Agonists

Main article: Beta₂-adrenergic agonist

Spasmolytics used in asthma and COPD

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)^[14]
- bambuterol
- clenbuterol
- formoterol
- salmeterol

Ultra-long-acting β₂ agonists (ultra-LABA)
- carmoterol
- indacaterol
- milveterol (GSK 159797)
- olodaterol
- vilanterol (GSK 642444)

Tocolytic agents

Short-acting β₂ agonists (SABA)
- fenoterol
- hexoprenaline
- isoxsuprine
- ritodrine
- salbutamol (INN) or albuterol (USAN)
- terbutaline

β₂ agonists used for other purposes

zilpaterol

Antagonists

(Beta blockers)

* denotes selective agonists to the receptor.

Interactions

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

References

1 2 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.
1 2 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.
↑ "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. Bibcode:2007Natur.450..383R. doi:10.1038/nature06325. PMID 17952055.
↑ 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. PMID 16574446.
↑ 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. Bibcode:2000BpJ....79.2547C. doi:10.1016/S0006-3495(00)76495-2. PMC 1301137. PMID 11053129.
↑ 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. PMID 12063255.
↑ 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. PMID 7540086.
1 2 3 4 5 Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 163
1 2 3 4 5 6 Fitzpatrick, David; Purves, Dale; Augustine, George (2004). "Table 20:2". Neuroscience (Third ed.). Sunderland, Mass: Sinauer. ISBN 0-87893-725-0.
↑ Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. p. 270. ISBN 0-443-07145-4.
↑ 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. PMID 11121511.
↑ Matera, MG; Cazzola, M (2007). "Ultra-Long-Acting β₂-Adrenoceptor Agonists: An Emerging Therapeutic Option for Asthma and COPD?". Drugs 67 (4): 503–15. doi:10.2165/00003495-200767040-00002. Retrieved 7 March 2016.
↑ 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. PMID 11309381.
↑ 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. PMID 9880537.
↑ 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. PMID 11278447.
↑ 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. PMID 9830057.
↑ 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. doi:10.1038/ncb2252. PMC 3113693. PMID 21602791.
↑ 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. PMID 11882663.
↑ 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. Bibcode:1998PNAS...95.8496H. doi:10.1073/pnas.95.15.8496. PMC 21104. PMID 9671706.
↑ 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. Bibcode:1998Natur.392..626H. doi:10.1038/33458. PMID 9560162.

External links

"β₂-adrenoceptor". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.

Cell surface receptor: G protein-coupled receptors

Class A: Rhodopsin like

Neurotransmitter

Adrenergic	α1 (A B D) α2 (A B C) β1 β2 β3

Purinergic	Adenosine (A1 A2A A2B A3) P2Y (1 2 4 5 6 8 9 10 11 12 13 14)

Serotonin	(all but 5-HT3) 5-HT1 (A B D E F) 5-HT2 (A B C) 5-HT (4 5A 6 7)

Other	Acetylcholine (M1 M2 M3 M4 M5) Dopamine (D1 D2 D3 D4 D5) Histamine (H1 H2 H3 H4) Melatonin (1A 1B 1C) TAAR (1 2 3 5 6 8 9)

Metabolites and
signaling molecules

Eicosanoid	CysLT (1 2) LTB4 (1 2) FPRL1 OXE Prostaglandin (DP (1 2), EP (1 2 3 4), FP) Prostacyclin Thromboxane

Other	Bile acid Cannabinoid (CB1 CB2, GPR (18 55 119)) EBI2 Estrogen Free fatty acid (1 2 3 4) Lactate Lysophosphatidic acid (1 2 3 4 5 6) Lysophospholipid (1 2 3 4 5 6 7 8) Niacin (1 2) Oxoglutarate PAF Sphingosine-1-phosphate (1 2 3 4 5) Succinate

Peptide

Neuropeptide	B/W (1 2) FF (1 2) S Y (1 2 4 5) Neuromedin (B U (1 2)) Neurotensin (1 2)

Other	Anaphylatoxin (C3a C5a) Angiotensin (1 2) Apelin Bombesin (BRS3 GRPR NMBR) Bradykinin (B1 B2) Chemokine Cholecystokinin (A B) Endothelin (A B) Formyl peptide (1 2 3) FSH Galanin (1 2 3) GHB receptor Gonadotropin-releasing hormone (1 2) Ghrelin Kisspeptin Luteinizing hormone/choriogonadotropin MAS (1 1L D E F G X1 X2 X3 X4) Melanocortin (1 2 3 4 5) MCHR (1 2) Motilin Opioid (Delta Kappa Mu Nociceptin & Zeta, but not Sigma) Orexin (1 2) Oxytocin Prokineticin (1 2) Prolactin-releasing peptide Relaxin (1 2 3 4) Somatostatin (1 2 3 4 5) Tachykinin (1 2 3) Thyrotropin Thyrotropin-releasing hormone Urotensin-II Vasopressin (1A 1B 2)

Miscellaneous

Orphan	GPR (1 3 4 6 12 15 17 18 19 20 21 22 23 25 26 27 31 32 33 34 35 37 39 42 44 45 50 52 55 61 62 63 65 68 75 77 78 81 82 83 84 85 87 88 92 101 103 109A 109B 119 120 132 135 137B 139 141 142 146 148 149 150 151 152 153 160 161 162 171 173 174 176 177 182 183)

Other	Adrenomedullin Olfactory Opsin (3 4 5 1LW 1MW 1SW RGR RRH) Protease-activated (1 2 3 4) SREB (1 2 3)

Class B: Secretin like

Adhesion	ADGRG (1 2 3 4 5 6 7)

Orphan	GPR (56 64 97 98 110 111 112 113 114 115 116 123 124 125 126 128 133 143 144 155 157)

Other	Brain-specific angiogenesis inhibitor (1 2 3) Cadherin (1 2 3) Calcitonin CALCRL CD97 Corticotropin-releasing hormone (1 2) EMR (1 2 3) Glucagon (GR GIPR GLP1R GLP2R) Growth hormone releasing hormone PACAPR1 GPR Latrophilin (1 2 3 ELTD1) Methuselah-like proteins Parathyroid hormone (1 2) Secretin Vasoactive intestinal peptide (1 2)

Class C: Metabotropic glutamate / pheromone

Taste	TAS1R (1 2 3) TAS2R (1 3 4 5 7 8 9 10 13 14 16 19 20 30 31 38 39 40 41 42 43 45 46 50 60)

Other	Calcium-sensing receptor GABA B (1 2) Glutamate receptor (Metabotropic glutamate (1 2 3 4 5 6 7 8)) GPRC6A GPR (156 158 179) RAIG (1 2 3 4)

Class F: Frizzled / Smoothened

Frizzled	Frizzled (1 2 3 4 5 6 7 8 9 10)

Smoothened	Smoothened

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Beta-2 adrenergic receptor

Gene

Structure

Mechanism

Function

Muscular system

Circulatory system

Eye

Digestive system

Other

Agonists

Spasmolytics used in asthma and COPD

Tocolytic agents

β₂ agonists used for other purposes

Antagonists

Interactions

See also

References

Further reading

External links

Beta-2 adrenergic receptor

Gene

Structure

Mechanism

Function

Muscular system

Circulatory system

Eye

Digestive system

Other

Agonists

Spasmolytics used in asthma and COPD

Tocolytic agents

β2 agonists used for other purposes

Antagonists

Interactions

See also

References

Further reading

External links

β₂ agonists used for other purposes