Beta-2 adrenergic receptor

The beta-2 adrenergic receptor (β₂ adrenoreceptor), also known as ADRB2, is a cell membrane-spanning beta-adrenergic receptor that interacts with (binds) epinephrine, a hormone and neurotransmitter (ligand synonym, adrenaline) whose signaling, via a downstream L-type calcium channel interaction, mediates physiologic responses such as smooth muscle relaxation and bronchodilation. Unlike other adrenergic receptors, norepinephrine does not produce β₂ receptor stimulation.

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.

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. 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.

Function

Actions of the β₂ receptor include:

Muscular system

Tissue/Effect		Function
Smooth muscle relaxation in:	uterus	inhibits labor
	GI tract (decreases motility)	Delay digestion during fight-or-flight response
	detrusor urinae muscle of bladder wall This effect is stronger than the alpha-1 receptor effect of contraction.	Delay need of micturition
	seminal tract
	bronchi	Facilitate respiration (agonists can be useful in treating asthma)
blood vessels dilates smaller coronary arteries, hepatic artery, arteries to skeletal muscle	Increase perfusion of target organs	needed during fight-or-flight
striated muscle	Tremor (via PKA mediated facilitation of presynaptic Ca2+ influx leading to acetylcholine release)
	Increased mass and contraction speed	fight-or-flight
	glycogenolysis	provide glucose fuel
pancreas	Insulin secretion	increases uptake of glucose by muscle

Circulatory system

• Heart muscle contraction
• Increase cardiac output (minor degree compared to β₁).
  • Increase heart rate in sinoatrial node (SA node) (chronotropic effect).
  • Increase 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 GI tract.
• Thickened secretions from salivary glands.
• Insulin secretion from pancreas

Other

• Inhibit histamine-release from mast cells.
• Increase protein content of secretions from lacrimal glands.
• Increase renin secretion from kidney.
• Receptor also present in cerebellum.
• Bronchiole dilation (targeted while treating asthma attacks)
• Involved in brain - immune - communication

Agonists

Main article: Beta₂-adrenergic agonist

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

* denotes selective agonists to the receptor.

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