Beta-2 adrenergic receptor


The beta-2 adrenergic receptor, also known as ADRB2, is a cell membrane-spanning beta-adrenergic receptor that binds epinephrine, a hormone and neurotransmitter whose signaling, via adenylate cyclase stimulation through trimeric Gs proteins, increased cAMP, and 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

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 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.

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 which then activates protein kinase A, and counterbalancing phosphatase PP2A. Protein kinase A then goes on to phosphorylate 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.

Function

Muscular system

The β2 adrenoreceptor has been correlated with anabolic properties and muscular hypertrophy with usage of agents such as oral clenbuterol as well as intravenous albuterol, though oral albuterol did not generate the same impacts on muscle mass, suggesting that drugs with a short half-life do not maintain sufficient activation to achieve these effects. Long-acting β2 agonists such as clenbuterol are frequently abused performance-enhancing drugs for their anabolic, lipolytic, and performance-enhancing effects. As a result, most of these agents are banned by WADA, though some are permissible under a therapeutic use exemption and are typically monitored for usage in athletes. Clenbuterol remains banned not as a beta-agonist, but rather an anabolic agent.
FunctionTissueBiological Role
Smooth muscle relaxation in:GI tract Inhibition of digestion
Smooth muscle relaxation in:BronchiFacilitation of respiration. Hence, beta-2 agonists can be useful in treating asthma.
Smooth muscle relaxation in:Detrusor urinae muscle of bladder wall This effect is stronger than the alpha-1 receptor effect of contraction.Inhibition of need for micturition
Smooth muscle relaxation in:UterusInhibition of labor
Smooth muscle relaxation in:Seminal tract
Increased perfusion and vasodilationBlood vessels and arteries to skeletal muscle including the smaller coronary arteries and hepatic arteryFacilitation of muscle contraction and motility
Increased mass and contraction speedStriated muscleFacilitation of muscle contraction and motility
Insulin and glucagon secretionPancreasIncreased blood glucose and uptake by skeletal muscle
GlycogenolysisIncreased blood glucose and uptake by skeletal muscle
TremorMotor nerve terminals. Tremor is mediated by PKA mediated facilitation of presynaptic Ca2+ influx leading to acetylcholine release.

Circulatory system

In the normal eye, beta-2 stimulation by salbutamol increases intraocular pressure via net:
In glaucoma, drainage is reduced or blocked completely. 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

Agonists

Spasmolytics used in [asthma] and COPD">Chronic obstructive pulmonary disease">COPD


* denotes selective antagonist to the receptor.

Allosteric modulators

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