Beta-2 adrenergic receptor

From Wikipedia, the free encyclopedia
ADRB2
2RH1.png
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesADRB2, ADRB2R, ADRBR, B2AR, BAR, BETA2AR, adrenoceptor beta 2
External IDsOMIM: 109690 MGI: 87938 HomoloGene: 30948 GeneCards: ADRB2
Orthologs
SpeciesHumanMouse
Entrez

154

11555

Ensembl

ENSG00000169252

ENSMUSG00000045730

UniProt

P07550

P18762

RefSeq (mRNA)

NM_000024

NM_007420

RefSeq (protein)

NP_000015

NP_031446

Location (UCSC)Chr 5: 148.83 – 148.83 MbChr 18: 62.18 – 62.18 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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 Gs proteins, increased cAMP, and downstream L-type calcium channel interaction, mediates physiologic responses such as smooth muscle relaxation and bronchodilation.[5]

Robert J.Lefkowitz[6] and Brian Kobilka[7] studied beta 2 adrenergic receptor as a model system which rewarded them the 2012 Nobel Prize in Chemistry[8] “for groundbreaking discoveries that reveal the inner workings of an important family of such receptors: G-protein-coupled-receptors”.

The official symbol for the human gene encoding the β2 adrenoreceptor is ADRB2.[9]

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.[10]

Structure[]

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-Gs 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]

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 (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 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.[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]

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.[20][21] Long-acting β2 agonists such as clenbuterol (not used clinically in the United States) are frequently abused performance-enhancing drugs for their anabolic, lipolytic, and performance-enhancing effects.[22] As a result, most of these agents are banned by WADA (World Anti-Doping Agency), 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.

Function Tissue Biological Role
Smooth muscle relaxation in: GI tract (decreases motility) Inhibition of digestion
Bronchi[23] Facilitation of respiration. Hence, beta-2 agonists can be useful in treating asthma.
Detrusor urinae muscle of bladder wall[24][25] This effect is stronger than the alpha-1 receptor effect of contraction. Inhibition of need for micturition
Uterus Inhibition of labor
Seminal tract[26]
Increased perfusion and vasodilation Blood vessels and arteries to skeletal muscle including the smaller coronary arteries[27] and hepatic artery Facilitation of muscle contraction and motility
Increased mass and contraction speed Striated muscle[26]
Insulin and glucagon secretion Pancreas[28] Increased blood glucose and uptake by skeletal muscle
Glycogenolysis[26]
Tremor Motor nerve terminals.[26] Tremor is mediated by PKA mediated facilitation of presynaptic Ca2+ influx leading to acetylcholine release.
Legend
  The function facilitates the fight-or-flight response.

Circulatory system[]

  • Heart muscle contraction
  • Increase cardiac output (minor degree compared to β1).
    • Increases heart rate[23] in sinoatrial node (SA node) (chronotropic effect).
    • Increases atrial cardiac muscle contractility. (inotropic effect).
    • Increases contractility and automaticity[23] 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.[23]
  • Glycogenolysis and lactate release in skeletal muscle.[23]
  • Contract sphincters of Gastrointestinal tract.
  • Thickened secretions from salivary glands.[23]
  • Insulin and glucagon secretion from pancreas.[28]

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 [29]

Ligands[]

Agonists[]

Beta-2 adrenergic receptor
Transduction mechanismsPrimary: Gs
Secondary: Gi/o
Primary endogenous agonistsepinephrine, norepinephrine
Agonistsisoprenaline, salbutamol, salmeterol, others
Antagonistscarvedilol, propranolol, labetalol, others
Inverse agonistsN/A
Positive allosteric modulatorsZn2+ (low concentrations)
Negative allosteric modulatorsZn2+ (high concentrations)
External resources
IUPHAR/BPS29
DrugBankP07550
HMDBHMDBP01634
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)
  • Ultra-long-acting β2 agonists (ultra-LABA)
    • carmoterol
    • indacaterol
    • (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*[26]
  • First generation (non-selective) β-blockers
  • ICI-118,551*
  • Propranolol

* denotes selective antagonist to the receptor.

Allosteric modulators[]

  • compound-6FA,[31] PAM at intracellular binding site

Interactions[]

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

See also[]

  • Other adrenergic receptors
  • Discovery and development of beta2 agonists

References[]

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Further reading[]

External links[]

  • "β2-adrenoceptor". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
  • 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.
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