Beta-2 adrenergic receptor

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 J. Lefkowitz and Brian Kobilka studied beta 2 adrenergic receptor as a model system which rewarded them the 2012 Nobel Prize in Chemistry “for groundbreaking discoveries that reveal the inner workings of an important family of such receptors: 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

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

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

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


 * AKAP12,
 * OPRD1,
 * Grb2,
 * SNX27 and
 * SLC9A3R1.