Beta-2 adrenergic receptor

ADRB2
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; OMA:ADRB2 - orthologs
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: 62.31 – 62.31 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, increases cAMP, and, via 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 earned 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.[citation needed] 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

Function Tissue Biological Role
Smooth muscle relaxation in: GI tract (decreases motility) Inhibition of digestion
Bronchi[20] Facilitation of respiration.
Detrusor urinae muscle of bladder wall[21][22] This effect is stronger than the alpha-1 receptor effect of contraction. Inhibition of need for micturition
Uterus Inhibition of labor
Seminal tract[23]
Increased perfusion and vasodilation Blood vessels and arteries to skeletal muscle including the smaller coronary arteries[24] and hepatic artery Facilitation of muscle contraction and motility
Increased mass and contraction speed Striated muscle[23]
Insulin and glucagon secretion Pancreas[25] Increased blood glucose and uptake by skeletal muscle
Glycogenolysis[23]
Tremor Motor nerve terminals.[23] 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.[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]

Circulatory system

Eye

In the normal eye, beta-2 stimulation by salbutamol increases intraocular pressure via net:

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

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 [31]

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

Tocolytic agents

β2 agonists used for other purposes

Antagonists

(Beta blockers)

* denotes selective antagonist to the receptor.

Allosteric modulators

  • compound-6FA,[33] PAM at intracellular binding site
  • Cellular swelling [34]

Interactions

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

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000169252 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000045730 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  6. ^ "The Nobel Prize in Chemistry 2012". NobelPrize.org. Retrieved 2021-07-04.
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Lleyton Hewitt

Lleyton HewittLleyton Hewitt nel 2018Nazionalità Australia Altezza178 cm Peso77 kg Tennis Termine carriera21 gennaio 2016 (singolare) 24 gennaio 2020 (doppio) Hall of fame (2021) Carriera Singolare1 Vittorie/sconfitte 616–262 (70,16%) Titoli vinti 30 Miglior ranking 1º (19 novembre 2001) Risultati nei tornei del Grande Slam  Australian Open F (2005)  Roland Garros QF (2001, 2004)  Wimbledon V (2002)  US Open V (2001) Altri tornei  Tour Finals V (2001, 20...

Arriva Scotland West

British bus operating company Arriva Scotland WestEast Lancs MaxCi bodied Scania N113CRL in Glasgow in 2002ParentArrivaFounded1985Ceased operation2012HeadquartersInchinnanService areaGlasgowRenfrewshireService typeBus operatorHubsInchinnanJohnstoneFleet194 (June 2009) Arriva Scotland West[1] was a bus company based in Inchinnan, near Paisley, Scotland. It was formed in 1997 as a rebranding of the former Clydeside 2000 company when purchased by Arriva. On 26 March 2012, the business wa...

 

 

Henry Cotterill

For the New Zealand cricket player, see Henry Cotterill (lawyer). The Right ReverendHenry CotterillBishop of EdinburghChurchScottish Episcopal ChurchIn office1872–1886PredecessorCharles TerrotSuccessorJohn DowdenOther post(s)Bishop of Grahamstown (1856–1871)bishop coadjutor of Edinburgh (1871–1872)OrdersOrdination1836Consecration1856Personal detailsBorn1812Ampton, Suffolk, EnglandDied(1886-04-16)16 April 1886Edinburgh, Edinburghshire, Scotland Henry Cotterill's grave in St Mary's Episco...