Beta-2 adrenergic receptor

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.^[10]

The 3D crystallographic structure (see figure and links to the right) of the β₂-adrenergic receptor has been determined^[11][12][13] 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.^[14]

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.^[15]

This receptor is directly associated with one of its ultimate effectors, the class C L-type calcium channel Ca_V1.2.^{[citation needed]} 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.^[16]

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.^[17] This appears to be mediated by cAMP induced PKA phosphorylation of the receptor.^[18]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 ^[19]

Activation of the β₂ adrenoreceptor with long-acting agents such as oral clenbuterol and intravenously-infused albuterol results in skeletomuscular hypertrophy and anabolism.^[26][27] 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.^[28] 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. ^[29][30]

• Heart muscle contraction
• Increase cardiac output (minor degree compared to β₁).
  • Increases heart rate^[20] in sinoatrial node (SA node) (chronotropic effect).
  • Increases atrial cardiac muscle contractility. (inotropic effect).
  • Increases contractility and automaticity^[20] of ventricular cardiac muscle.
• Dilate hepatic artery.
• Dilate arterioles to skeletal muscle.

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.

• Glycogenolysis and gluconeogenesis in liver.^[20]
• Glycogenolysis and lactate release in skeletal muscle.^[20]
• Contract sphincters of Gastrointestinal tract.
• Thickened secretions from salivary glands.^[20]
• Insulin and glucagon secretion from pancreas.^[25]

• 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 ^[31]

• 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)^[32]
  • bambuterol
  • clenbuterol
  • formoterol
  • salmeterol
• Ultra-long-acting β₂ agonists (ultra-LABA)
  • carmoterol
  • indacaterol
  • milveterol (GSK 159797)
  • olodaterol
  • vilanterol (GSK 642444)

• Short-acting β₂ agonists (SABA)
  • fenoterol
  • hexoprenaline
  • isoxsuprine
  • ritodrine
  • salbutamol (INN) or albuterol (USAN)
  • terbutaline

• zilpaterol

(Beta blockers)

• butoxamine*^[23]
• First generation (non-selective) β-blockers
• ICI-118,551*
• Propranolol

* denotes selective antagonist to the receptor.

• compound-6FA,^[33] PAM at intracellular binding site

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

• 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

• "β₂-adrenoceptor". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2015-01-12. Retrieved 2008-11-25.
• Human ADRB2 genome location and ADRB2 gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: P07550 ( Beta-2 adrenergic receptor) at the PDBe-KB.