β2-adrenergic Receptors

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 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

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

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External links

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{{G protein-coupled receptors, g1

Adrenergic receptors