Beta-2 adrenergic receptor

Template:Short description Template:Cs1 configTemplate:Infobox gene 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 G_s 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 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.

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-G_s 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 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 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 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. 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

Function	Tissue	Biological Role
Smooth 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 micturition
	Uterus	Inhibition of labor
	Seminal tract
Increased perfusion and vasodilation	Blood vessels and arteries to skeletal muscle including the smaller coronary arteries and hepatic artery	Facilitation of muscle contraction and motility
Increased mass and contraction speed	Striated muscle
Insulin and glucagon secretion	Pancreas	Increased blood glucose and uptake by skeletal muscle
Glycogenolysis
Tremor	Motor nerve terminals. Tremor is mediated by PKA mediated facilitation of presynaptic Ca2+ influx leading to acetylcholine release.

Legend   The function facilitates the fight-or-flight response.

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: Template:Div col

• 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

External links

• Template:UCSC gene info
• Template:PDBe-KB2