The beta-2 adrenergic receptor (β2 adrenoreceptor), also known as ADRB2, is a cell membrane-spanning beta-adrenergic receptor that binds epinephrine (adrenaline), a hormone and neurotransmitter whose signaling, via adenylate cyclase stimulation through trimeric Gs proteins, increases cAMP, and, via downstream L-type calcium channel interaction, mediates physiologic responses such as smooth muscle relaxation and bronchodilation.

Robert Lefkowitz and Brian Kobilka's study of the beta-2 adrenergic receptor as a model system earned them the 2012 Nobel Prize in Chemistry "for studies of G-protein-coupled receptors".

The official symbol for the human gene encoding the β2 adrenoreceptor is ADRB2.

Gene The gene is intronless. Different polymorphic forms, point mutations, and/or downregulation of this gene are associated with nocturnal asthma, obesity and type 2 diabetes.

Structure 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.

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.

Mechanism 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 counterbalancing phosphatase PP2A. 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. 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

Function

FunctionTissueBiological roleSmooth muscle relaxation in: GI tract (decreases motility) Inhibition of digestion Bronchi Facilitation of respiration.Relaxes Detrusor urinae muscle of bladder wall This effect is stronger than the alpha-1 receptor effect of contraction.Inhibition of need for micturitionUterusInhibition of laborSeminal tract Page 163 Increased perfusion and vasodilationBlood vessels and arteries to skeletal muscle including the smaller coronary arteries and hepatic arteryFacilitation of muscle contraction and motilityIncreased mass and contraction speedStriated muscle Insulin and glucagon secretion Pancreas Increased blood glucose and uptake by skeletal muscleGlycogenolysis TremorMotor nerve terminals. Tremor is mediated by PKA mediated facilitation of presynaptic Ca2+ influx leading to acetylcholine release. Legend

Musculoskeletal system Activation of the β2 adrenoreceptor with long-acting agents such as oral clenbuterol and intravenously-infused albuterol results in skeletomuscular hypertrophy and anabolism. 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. 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.

Circulatory system Heart muscle contraction Increase cardiac output (minor degree compared to β1). Increases heart rate in sinoatrial node (SA node) (chronotropic effect). Increases atrial cardiac muscle contractility. (inotropic effect). Increases contractility and automaticity 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. Glycogenolysis and lactate release in skeletal muscle. Contract sphincters of Gastrointestinal tract. Thickened secretions from salivary glands. Insulin and glucagon secretion from pancreas.

Other Inhibit histamine-release from mast cells. Increase protein content of secretions from lacrimal glands. Receptor also present in cerebellum. Bronchiole dilation (targeted while treating asthma attacks) Involved in brain - immune - communication

Ligands Agonists

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) 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) butoxamine* First generation (non-selective) β-blockers ICI-118,551* Propranolol

* denotes selective antagonist to the receptor.

Allosteric modulators compound-6FA, PAM at intracellular binding site Cellular swelling

Interactions

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

AKAP12, OPRD1, Grb2, SNX27 and SLC9A3R1.

See also Other adrenergic receptors Alpha-1 adrenergic receptor Alpha-2 adrenergic receptor Beta-1 adrenergic receptor Beta-3 adrenergic receptor Discovery and development of beta2 agonists

References

Further reading

External links