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{{Short description|Mammalian protein found in humans}}
{{Infobox_gene}}
{{cs1 config|name-list-style=vanc}}{{Infobox_gene}}
The '''beta-2 adrenergic receptor''' (β<sub>2</sub> adrenoreceptor), also known as '''ADRB2''', is a cell membrane-spanning [[beta-adrenergic receptor]] that interacts with ([[ligand binding|binds]]) [[epinephrine]], a hormone and [[neurotransmitter]] (ligand synonym, [[adrenaline]]) whose signaling, via [[adenylate cyclase]] stimulation through trimeric Gs proteins, increased [[Cyclic adenosine monophosphate|cAMP]], and downstream [[L-type calcium channel]] interaction, mediates physiologic responses such as [[Beta2-adrenergic agonist|smooth muscle relaxation and bronchodilation]].<ref name="pmid16387578">{{cite journal | vauthors = Johnson M | title = Molecular mechanisms of beta(2)-adrenergic receptor function, response, and regulation | journal = The Journal of Allergy and Clinical Immunology | volume = 117 | issue = 1 | pages = 18–24; quiz 25 | date = January 2006 | pmid = 16387578 | doi = 10.1016/j.jaci.2005.11.012 | doi-access = free }}</ref>
The '''beta-2 adrenergic receptor''' (β<sub>2</sub> adrenoreceptor), also known as '''ADRB2''', is a cell membrane-spanning [[beta-adrenergic receptor]] that [[ligand binding|binds]] [[epinephrine]] (adrenaline), a hormone and [[neurotransmitter]] whose signaling, via [[adenylate cyclase]] stimulation through [[heterotrimeric G protein|trimeric G<sub>s</sub> protein]]s, increases [[Cyclic adenosine monophosphate|cAMP]], and, via downstream [[L-type calcium channel]] interaction, mediates physiologic responses such as [[smooth muscle]] relaxation and bronchodilation.<ref name="pmid16387578">{{cite journal | vauthors = Johnson M | title = Molecular mechanisms of beta(2)-adrenergic receptor function, response, and regulation | journal = The Journal of Allergy and Clinical Immunology | volume = 117 | issue = 1 | pages = 18–24; quiz 25 | date = January 2006 | pmid = 16387578 | doi = 10.1016/j.jaci.2005.11.012 | doi-access = }}</ref>


Robert J. Lefkowitz<ref>{{cite web|title=The Nobel Prize in Chemistry 2012|url=https://www.nobelprize.org/prizes/chemistry/2012/lefkowitz/facts/|access-date=2021-07-04|website=NobelPrize.org|language=en-US}}</ref> and Brian Kobilka<ref>{{cite web|title=The Nobel Prize in Chemistry 2012|url=https://www.nobelprize.org/prizes/chemistry/2012/kobilka/facts/|access-date=2021-07-04|website=NobelPrize.org|language=en-US}}</ref> studied beta 2 adrenergic receptor as a model system which earned them the 2012 Nobel Prize in Chemistry<ref>{{cite web|title=The Nobel Prize in Chemistry 2012|url=https://www.nobelprize.org/prizes/chemistry/2012/summary/|access-date=2021-07-04|website=NobelPrize.org|language=en-US}}</ref> “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 β<sub>2</sub> adrenoreceptor is ADRB2.<ref name="entrez">{{cite web | title = Entrez Gene: ADRB2 adrenoceptor beta 2, surface | url = https://www.ncbi.nlm.nih.gov/gene/154 | accessdate = 8 February 2015}}</ref>

⚫
The official symbol for the human [[gene]] encoding the β<sub>2</sub> adrenoreceptor is ''ADRB2''.<ref name="entrez">{{cite web | title = Entrez Gene: ADRB2 adrenoceptor beta 2, surface | url = https://www.ncbi.nlm.nih.gov/gene/154 | access-date = 8 February 2015}}</ref>


==Gene==
==Gene==
The {{gene|ADRB2}} gene is [[intron]]less. Different polymorphic forms, [[point mutation]]s, and/or [[gene downregulation|downregulation]] of this gene are associated with nocturnal [[asthma]], [[obesity]] and [[type 2 diabetes]].<ref>{{cite web | title = Entrez Gene: ADRB2 adrenergic, beta-2-, receptor, surface| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=154| accessdate = }}</ref>
The {{gene|ADRB2}} gene is [[intron]]less. Different polymorphic forms, [[point mutation]]s, and/or [[gene downregulation|downregulation]] of this gene are associated with nocturnal [[asthma]], [[obesity]] and [[type 2 diabetes]].<ref>{{cite web | title = Entrez Gene: ADRB2 adrenergic, beta-2-, receptor, surface| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=154}}</ref>


==Structure==
==Structure==
The 3D crystallographic structure (see figure and links to the right) of the β<sub>2</sub>-adrenergic receptor has been determined<ref name="Cherezov_2007">{{cite journal |vauthors=Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC | title = High-resolution crystal structure of an engineered human β<sub>2</sub>-adrenergic G protein-coupled receptor | journal = Science | volume = 318 | issue = 5854 | pages = 1258–65 | year = 2007 | pmid = 17962520 | doi = 10.1126/science.1150577 | issn = | pmc=2583103| bibcode = 2007Sci...318.1258C }}</ref><ref name="Rosenbaum_2007">{{cite journal |vauthors=Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK | title = GPCR engineering yields high-resolution structural insights into β<sub>2</sub>-adrenergic receptor function | journal = Science | volume = 318 | issue = 5854 | pages = 1266–73 | year = 2007 | pmid = 17962519 | doi = 10.1126/science.1150609 | issn = | bibcode = 2007Sci...318.1266R }}</ref><ref name="Rasmussen_2007">{{cite journal | vauthors = Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK | title = Crystal structure of the human beta2 adrenergic G-protein-coupled receptor | journal = Nature | volume = 450 | issue = 7168 | pages = 383–7 | date = Nov 2007 | pmid = 17952055 | doi = 10.1038/nature06325 | bibcode = 2007Natur.450..383R }}</ref> 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.<ref>{{Cite journal|last=Liszewski|first=Kathy|date=1 October 2015|title=Dissecting the Structure of Membrane Proteins|url=http://www.genengnews.com/gen-articles/dissecting-the-structure-of-membrane-proteins/5583/|journal=[[Gen. Eng. Biotechnol. News|Genetic Engineering & Biotechnology News]]|volume=35|issue=17|page=16|type=paper|doi=10.1089/gen.35.07.09}}{{subscription required}}</ref>
The 3D crystallographic structure (see figure and links to the right) of the β<sub>2</sub>-adrenergic receptor has been determined<ref name="Cherezov_2007">{{cite journal |vauthors=Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC | title = High-resolution crystal structure of an engineered human β<sub>2</sub>-adrenergic G protein-coupled receptor | journal = Science | volume = 318 | issue = 5854 | pages = 1258–65 | year = 2007 | pmid = 17962520 | doi = 10.1126/science.1150577 | pmc=2583103| bibcode = 2007Sci...318.1258C }}</ref><ref name="Rosenbaum_2007">{{cite journal |vauthors=Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK | title = GPCR engineering yields high-resolution structural insights into β<sub>2</sub>-adrenergic receptor function | journal = Science | volume = 318 | issue = 5854 | pages = 1266–73 | year = 2007 | pmid = 17962519 | doi = 10.1126/science.1150609 | bibcode = 2007Sci...318.1266R | s2cid = 1559802 | doi-access = free }}</ref><ref name="Rasmussen_2007">{{cite journal | vauthors = Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK | title = Crystal structure of the human beta2 adrenergic G-protein-coupled receptor | journal = Nature | volume = 450 | issue = 7168 | pages = 383–7 | date = Nov 2007 | pmid = 17952055 | doi = 10.1038/nature06325 | bibcode = 2007Natur.450..383R | s2cid = 4407117 }}</ref> 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.<ref>{{cite journal| vauthors = Liszewski K |date=1 October 2015|title=Dissecting the Structure of Membrane Proteins|url=http://www.genengnews.com/gen-articles/dissecting-the-structure-of-membrane-proteins/5583/|journal=[[Gen. Eng. Biotechnol. News|Genetic Engineering & Biotechnology News]]|volume=35|issue=17|page=16|type=paper|doi=10.1089/gen.35.07.09|url-access=subscription}}{{subscription required}}</ref>

The crystal structure of the β<sub>2</sub>Adrenergic Receptor-G<sub>s</sub> 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.<ref>{{cite journal | vauthors = Rasmussen SG, DeVree BT, Zou Y, Kruse AC, Chung KY, Kobilka TS, Thian FS, Chae PS, Pardon E, Calinski D, Mathiesen JM, Shah ST, Lyons JA, Caffrey M, Gellman SH, Steyaert J, Skiniotis G, Weis WI, Sunahara RK, Kobilka BK | display-authors = 6 | title = Crystal structure of the β2 adrenergic receptor-Gs protein complex | journal = Nature | volume = 477 | issue = 7366 | pages = 549–55 | date = July 2011 | pmid = 21772288 | pmc = 3184188 | doi = 10.1038/nature10361 | bibcode = 2011Natur.477..549R }}</ref>


==Mechanism==
==Mechanism==
This receptor is directly associated with one of its ultimate effectors, the class C [[L-type calcium channel]] Ca<sub>V</sub>1.2. This receptor-channel complex is [[G protein-coupled receptor|coupled]] to the [[Gs alpha subunit|G<sub>s</sub>]] [[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.<ref name="pmid16574446">{{cite journal | vauthors = Rubenstein LA, Zauhar RJ, Lanzara RG | title = Molecular dynamics of a biophysical model for beta2-adrenergic and G protein-coupled receptor activation | journal = Journal of Molecular Graphics & Modelling | volume = 25 | issue = 4 | pages = 396–409 | date = Dec 2006 | pmid = 16574446 | doi = 10.1016/j.jmgm.2006.02.008 }}</ref>
This receptor is directly associated with one of its ultimate effectors, the class C [[L-type calcium channel]] Ca<sub>V</sub>1.2.{{citation needed|date=September 2023}} This receptor-channel complex is [[G protein-coupled receptor|coupled]] to the [[Gs alpha subunit|G<sub>s</sub>]] [[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.<ref name="pmid16574446">{{cite journal | vauthors = Rubenstein LA, Zauhar RJ, Lanzara RG | title = Molecular dynamics of a biophysical model for beta2-adrenergic and G protein-coupled receptor activation | journal = Journal of Molecular Graphics & Modelling | volume = 25 | issue = 4 | pages = 396–409 | date = Dec 2006 | pmid = 16574446 | doi = 10.1016/j.jmgm.2006.02.008 }}</ref>


Beta-2 adrenergic receptors have also been found to couple with [[Gi alpha subunit|G<sub>i</sub>]], 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<sub>s</sub>, and stimulation of these results in a more diffuse cellular response.<ref name="pmid11053129">{{cite journal | vauthors = Chen-Izu Y, Xiao RP, Izu LT, Cheng H, Kuschel M, Spurgeon H, Lakatta EG | title = G(i)-dependent localization of beta(2)-adrenergic receptor signaling to L-type Ca(2+) channels | journal = Biophysical Journal | volume = 79 | issue = 5 | pages = 2547–56 | date = Nov 2000 | pmid = 11053129 | pmc = 1301137 | doi = 10.1016/S0006-3495(00)76495-2 | bibcode = 2000BpJ....79.2547C }}</ref> This appears to be mediated by cAMP induced PKA phosphorylation of the receptor.<ref name="pmid12063255">{{cite journal | vauthors = Zamah AM, Delahunty M, Luttrell LM, Lefkowitz RJ | title = Protein kinase A-mediated phosphorylation of the beta 2-adrenergic receptor regulates its coupling to Gs and Gi. Demonstration in a reconstituted system | journal = The Journal of Biological Chemistry | volume = 277 | issue = 34 | pages = 31249–56 | date = Aug 2002 | pmid = 12063255 | doi = 10.1074/jbc.M202753200 | doi-access = free }}</ref>
Beta-2 adrenergic receptors have also been found to couple with [[Gi alpha subunit|G<sub>i</sub>]], 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<sub>s</sub>, and stimulation of these results in a more diffuse cellular response.<ref name="pmid11053129">{{cite journal | vauthors = Chen-Izu Y, Xiao RP, Izu LT, Cheng H, Kuschel M, Spurgeon H, Lakatta EG | title = G(i)-dependent localization of beta(2)-adrenergic receptor signaling to L-type Ca(2+) channels | journal = Biophysical Journal | volume = 79 | issue = 5 | pages = 2547–56 | date = Nov 2000 | pmid = 11053129 | pmc = 1301137 | doi = 10.1016/S0006-3495(00)76495-2 | bibcode = 2000BpJ....79.2547C }}</ref> This appears to be mediated by cAMP induced PKA phosphorylation of the receptor.<ref name="pmid12063255">{{cite journal | vauthors = Zamah AM, Delahunty M, Luttrell LM, Lefkowitz RJ | title = Protein kinase A-mediated phosphorylation of the beta 2-adrenergic receptor regulates its coupling to Gs and Gi. Demonstration in a reconstituted system | journal = The Journal of Biological Chemistry | volume = 277 | issue = 34 | pages = 31249–56 | date = Aug 2002 | pmid = 12063255 | doi = 10.1074/jbc.M202753200 | doi-access = free }}</ref>
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 <ref>{{cite journal | vauthors = Bathe-Peters M, Gmach P, Boltz HH, Einsiedel J, Gotthardt M, Hübner H, Gmeiner P, Lohse MJ, Annibale P | display-authors = 6 | title = Visualization of β-adrenergic receptor dynamics and differential localization in cardiomyocytes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 118 | issue = 23 | page = e2101119118 | date = June 2021 | pmid = 34088840 | doi = 10.1073/pnas.2101119118|issn=0027-8424 | pmc = 8201832 | doi-access = free | bibcode = 2021PNAS..11801119B }}</ref>


== Function ==
== Function ==
Actions of the β<sub>2</sub> receptor include:
<!--Actions of the β<sub>2</sub> receptor include:-->


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===Muscular system===

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The β<sub>2</sub> 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.<ref>{{cite journal | vauthors = Choo JJ, Horan MA, Little RA, Rothwell NJ | title = Anabolic effects of clenbuterol on skeletal muscle are mediated by beta 2-adrenoceptor activation | journal = The American Journal of Physiology | volume = 263 | issue = 1 Pt 1 | pages = E50-6 | date = July 1992 | pmid = 1322047 | doi = 10.1152/ajpendo.1992.263.1.E50 }}</ref><ref>{{cite journal | vauthors = Kamalakkannan G, Petrilli CM, George I, LaManca J, McLaughlin BT, Shane E, Mancini DM, Maybaum S | display-authors = 6 | title = Clenbuterol increases lean muscle mass but not endurance in patients with chronic heart failure | journal = The Journal of Heart and Lung Transplantation | volume = 27 | issue = 4 | pages = 457–61 | date = April 2008 | pmid = 18374884 | doi = 10.1016/j.healun.2008.01.013 }}</ref> Long-acting β<sub>2</sub> 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.<ref>{{cite journal | vauthors = Davis E, Loiacono R, Summers RJ | title = The rush to adrenaline: drugs in sport acting on the beta-adrenergic system | journal = British Journal of Pharmacology | volume = 154 | issue = 3 | pages = 584–97 | date = June 2008 | pmid = 18500380 | pmc = 2439523 | doi = 10.1038/bjp.2008.164 }}</ref> 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.
{|class="wikitable"
{|class="wikitable"
!Function
!Function
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| style="background: LemonChiffon"| Inhibition of [[digestion]]
| style="background: LemonChiffon"| Inhibition of [[digestion]]
|-
|-
| [[Bronchi]]<ref name="purves">{{cite book | last1 = Fitzpatrick | first1 = David | last2 = Purves | first2 = Dale | last3 = Augustine | first3 = George | name-list-format = vanc | title = Neuroscience | publisher = Sinauer | location = Sunderland, Mass | year = 2004 | edition = Third | chapter = Table 20:2 | pages = | isbn = 978-0-87893-725-7 | oclc = | doi = }}</ref>
| [[Bronchi]]<ref name="purves">{{cite book | vauthors = Fitzpatrick D, Purves D, Augustine G | title = Neuroscience | publisher = Sinauer | location = Sunderland, Mass | year = 2004 | edition = Third | chapter = Table 20:2 | isbn = 978-0-87893-725-7 }}</ref>
| style="background: LemonChiffon"| Facilitation of [[respiration (physiology)|respiration]]. Hence, beta-2 agonists can be useful in treating [[asthma]].
| style="background: LemonChiffon"| Facilitation of [[respiration (physiology)|respiration]].
|-
|-
|[[Detrusor urinae muscle]] of [[Urinary bladder|bladder]] wall<ref name="pmid7540086">{{cite journal | vauthors = von Heyden B, Riemer RK, Nunes L, Brock GB, Lue TF, Tanagho EA | title = Response of guinea pig smooth and striated urethral sphincter to cromakalim, prazosin, nifedipine, nitroprusside, and electrical stimulation | journal = Neurourology and Urodynamics | volume = 14 | issue = 2 | pages = 153–68 | year = 1995 | pmid = 7540086 | doi = 10.1002/nau.1930140208 }}</ref><ref name="Moro et al. 2013">{{cite journal | vauthors = Moro C, Tajouri L, Chess-Williams R | title = Adrenoceptor function and expression in bladder urothelium and lamina propria | journal = Urology | volume = 81 | issue = 1 | pages = 211.e1–7 | date = January 2013 | pmid = 23200975 | doi = 10.1016/j.urology.2012.09.011 }}</ref> This effect is stronger than the [[alpha-1 receptor]] effect of contraction.
|[[Detrusor urinae muscle]] of [[Urinary bladder|bladder]] wall<ref name="pmid7540086">{{cite journal | vauthors = von Heyden B, Riemer RK, Nunes L, Brock GB, Lue TF, Tanagho EA | title = Response of guinea pig smooth and striated urethral sphincter to cromakalim, prazosin, nifedipine, nitroprusside, and electrical stimulation | journal = Neurourology and Urodynamics | volume = 14 | issue = 2 | pages = 153–68 | year = 1995 | pmid = 7540086 | doi = 10.1002/nau.1930140208 | s2cid = 31114890 }}</ref><ref name="Moro et al. 2013">{{cite journal | vauthors = Moro C, Tajouri L, Chess-Williams R | title = Adrenoceptor function and expression in bladder urothelium and lamina propria | journal = Urology | volume = 81 | issue = 1 | pages = 211.e1–7 | date = January 2013 | pmid = 23200975 | doi = 10.1016/j.urology.2012.09.011 }}</ref> This effect is stronger than the [[alpha-1 receptor]] effect of contraction.
|Inhibition of need for [[micturition]]
|Inhibition of need for [[micturition]]
|-
|-
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|Inhibition of labor
|Inhibition of labor
|-
|-
|[[Seminal tract]]<ref name=Rang163>{{cite book | vauthors = Rang HP |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |pages= |isbn=978-0-443-07145-4 |oclc= |doi=}} Page 163</ref>
|[[Seminal tract]]<ref name=Rang163>{{cite book | vauthors = Rang HP |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |isbn=978-0-443-07145-4 }} Page 163</ref>
|
|
|-
|-
| Increased [[perfusion]] and [[vasodilation]]
| Increased [[perfusion]] and [[vasodilation]]
|[[Blood vessels]] and [[arteries]] to [[skeletal muscle]] including the smaller [[Right coronary artery|coronary arteries]]<ref name=Rang270>{{cite book | vauthors = Rang HP |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |isbn=978-0-443-07145-4 |oclc= |doi=| page = 270}}</ref> and [[hepatic artery proper|hepatic artery]]
|[[Blood vessels]] and [[arteries]] to [[skeletal muscle]] including the smaller [[Right coronary artery|coronary arteries]]<ref name=Rang270>{{cite book | vauthors = Rang HP |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |isbn=978-0-443-07145-4 | page = 270}}</ref> and [[hepatic artery proper|hepatic artery]]
|rowspan=2 style="background: lemonchiffon"|Facilitation of muscle contraction and motility
|rowspan=2 style="background: lemonchiffon"|Facilitation of muscle contraction and motility
|-
|-
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|-
|-
| [[Insulin]] and [[glucagon]] secretion
| [[Insulin]] and [[glucagon]] secretion
| Pancreas<ref name="Philipson S313–317">{{Cite journal|last=Philipson|first=L. H.|date=December 2002|title=beta-Agonists and metabolism|journal=The Journal of Allergy and Clinical Immunology|volume=110|issue=6 Suppl|pages=S313–317|issn=0091-6749|pmid=12464941|doi=10.1067/mai.2002.129702}}</ref>
| Pancreas<ref name="Philipson S313–317">{{cite journal | vauthors = Philipson LH | title = beta-Agonists and metabolism | journal = The Journal of Allergy and Clinical Immunology | volume = 110 | issue = 6 Suppl | pages = S313-7 | date = December 2002 | pmid = 12464941 | doi = 10.1067/mai.2002.129702 }}</ref>
|rowspan=2 style="background: LemonChiffon"| Increased blood [[glucose]] and uptake by skeletal muscle
|rowspan=2 style="background: LemonChiffon"| Increased blood [[glucose]] and uptake by skeletal muscle
|-
|-
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}}
}}
|}
|}
⚫
===Musculoskeletal system===

⚫
Activation of the β<sub>2</sub> adrenoreceptor with long-acting agents such as oral [[clenbuterol]] and intravenously-infused [[albuterol]] results in skeletomuscular hypertrophy and anabolism.<ref>{{cite journal | vauthors = Choo JJ, Horan MA, Little RA, Rothwell NJ | title = Anabolic effects of clenbuterol on skeletal muscle are mediated by beta 2-adrenoceptor activation | journal = The American Journal of Physiology | volume = 263 | issue = 1 Pt 1 | pages = E50-6 | date = July 1992 | pmid = 1322047 | doi = 10.1152/ajpendo.1992.263.1.E50 }}</ref><ref>{{cite journal | vauthors = Kamalakkannan G, Petrilli CM, George I, LaManca J, McLaughlin BT, Shane E, Mancini DM, Maybaum S | display-authors = 6 | title = Clenbuterol increases lean muscle mass but not endurance in patients with chronic heart failure | journal = The Journal of Heart and Lung Transplantation | volume = 27 | issue = 4 | pages = 457–61 | date = April 2008 | pmid = 18374884 | doi = 10.1016/j.healun.2008.01.013 }}</ref> The comprehensive anabolic, lipolytic, and ergogenic effects of long-acting β<sub>2</sub> agonists such as clenbuterol render them frequent targets as performance-enhancing drugs in athletes.<ref>{{cite journal | vauthors = Davis E, Loiacono R, Summers RJ | title = The rush to adrenaline: drugs in sport acting on the beta-adrenergic system | journal = British Journal of Pharmacology | volume = 154 | issue = 3 | pages = 584–97 | date = June 2008 | pmid = 18500380 | pmc = 2439523 | doi = 10.1038/bjp.2008.164 }}</ref> 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 β<sub>2</sub> adrenergic agents remain banned not as a beta-agonist, but rather an anabolic agent. These effects are largely attractive within agricultural contexts insofar that β<sub>2</sub> 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. <ref>{{cite web |title=Clenbuterol |url=https://www.deadiversion.usdoj.gov/drug_chem_info/clenbuterol.pdf |website=Drug and Chemical Evaluation Section |publisher=Drug Enforcement Agency |access-date=15 November 2021}}</ref><ref>{{cite web |title=Food and Drugs - ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS |url=https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=530.41 |publisher=U.S. Food and Drug Administration |access-date=15 November 2021}}</ref>


===Circulatory system===
===Circulatory system===
* Heart muscle contraction
* Heart muscle contraction
* Increase [[cardiac output]] (minor degree compared to β<sub>1</sub>).
* Increase [[cardiac output]] (minor degree compared to β<sub>1</sub>).
**Increases [[heart rate]] <ref name=purves/> in [[sinoatrial node]] (SA node) ([[chronotropic]] effect).
**Increases [[heart rate]]<ref name=purves/> in [[sinoatrial node]] (SA node) ([[chronotropic]] effect).
**Increases [[heart atrium|atrial]] [[cardiac muscle]] contractility. ([[inotropic]] effect).
**Increases [[heart atrium|atrial]] [[cardiac muscle]] contractility. ([[inotropic]] effect).
**Increases contractility and [[cardiac muscle automaticity|automaticity]]<ref name=purves/> of [[heart ventricle|ventricular]] cardiac muscle.
**Increases contractility and [[cardiac muscle automaticity|automaticity]]<ref name=purves/> of [[heart ventricle|ventricular]] cardiac muscle.
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* Receptor also present in [[cerebellum]].
* Receptor also present in [[cerebellum]].
* Bronchiole dilation (targeted while treating asthma attacks)
* Bronchiole dilation (targeted while treating asthma attacks)
* Involved in brain - immune - communication <ref name="Elenkov">{{cite journal | vauthors = Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES | title = The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system | journal = Pharmacological Reviews | volume = 52 | issue = 4 | pages = 595–638 | date = Dec 2000 | pmid = 11121511 | doi = }}</ref>
* Involved in brain - immune - communication <ref name="Elenkov">{{cite journal | vauthors = Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES | title = The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system | journal = Pharmacological Reviews | volume = 52 | issue = 4 | pages = 595–638 | date = Dec 2000 | pmid = 11121511 }}</ref>


==Ligands==
==Ligands==
Line 127: Line 133:
** [[terbutaline]]
** [[terbutaline]]
* Long-acting β<sub>2</sub> agonists (LABA)
* Long-acting β<sub>2</sub> agonists (LABA)
** [[arformoterol]] (some consider it to be an ultra-LABA)<ref>{{cite journal | vauthors = Matera MG, Cazzola M | title = ultra-long-acting beta2-adrenoceptor agonists: an emerging therapeutic option for asthma and COPD? | journal = Drugs | volume = 67 | issue = 4 | pages = 503–15 | date = 2007 | pmid = 17352511 | doi = 10.2165/00003495-200767040-00002 }}</ref>
** [[arformoterol]] (some consider it to be an ultra-LABA)<ref>{{cite journal | vauthors = Matera MG, Cazzola M | title = ultra-long-acting beta2-adrenoceptor agonists: an emerging therapeutic option for asthma and COPD? | journal = Drugs | volume = 67 | issue = 4 | pages = 503–15 | date = 2007 | pmid = 17352511 | doi = 10.2165/00003495-200767040-00002 | s2cid = 46976912 }}</ref>
** [[bambuterol]]
** [[bambuterol]]
** [[clenbuterol]]
** [[clenbuterol]]
Line 161: Line 167:


===Allosteric modulators===
===Allosteric modulators===
* compound-6FA,<ref>{{cite journal |pmid=31249059|pmc=6705129|year=2019|last1=Liu|first1=X.|title=Mechanism of β<sub>2</sub>AR regulation by an intracellular positive allosteric modulator|journal=Science|volume=364|issue=6447|pages=1283–1287|last2=Masoudi|first2=A.|last3=Kahsai|first3=A. W.|last4=Huang|first4=L. Y.|last5=Pani|first5=B.|last6=Staus|first6=D. P.|last7=Shim|first7=P. J.|last8=Hirata|first8=K.|last9=Simhal|first9=R. K.|last10=Schwalb|first10=A. M.|last11=Rambarat|first11=P. K.|last12=Ahn|first12=S.|last13=Lefkowitz|first13=R. J.|last14=Kobilka|first14=B.|doi=10.1126/science.aaw8981|bibcode=2019Sci...364.1283L}}</ref> PAM at intracellular binding site
* compound-6FA,<ref>{{cite journal | vauthors = Liu X, Masoudi A, Kahsai AW, Huang LY, Pani B, Staus DP, Shim PJ, Hirata K, Simhal RK, Schwalb AM, Rambarat PK, Ahn S, Lefkowitz RJ, Kobilka B | display-authors = 6 | title = Mechanism of β<sub>2</sub>AR regulation by an intracellular positive allosteric modulator | journal = Science | volume = 364 | issue = 6447 | pages = 1283–1287 | date = June 2019 | pmid = 31249059 | pmc = 6705129 | doi = 10.1126/science.aaw8981 | bibcode = 2019Sci...364.1283L }}</ref> PAM at intracellular binding site
* Cellular swelling <ref>{{cite journal | vauthors = Sirbu A, Bathe-Peters M, Kumar J, Inoue A, Lohse MJ, Annibale P | title = Cell swelling enhances ligand-driven β-adrenergic signaling | journal = Nature Communications | volume = 15 | issue = 1 | pages = 1-12 | date = August 2024 | doi = 10.1038/s41467-024-52191-y| pmc = 11379887 }}</ref>


== Interactions ==
== Interactions ==
Line 171: Line 178:
* [[Grb2]],<ref name = pmid9830057>{{cite journal | vauthors = Karoor V, Wang L, Wang HY, Malbon CC | title = Insulin stimulates sequestration of beta-adrenergic receptors and enhanced association of beta-adrenergic receptors with Grb2 via tyrosine 350 | journal = The Journal of Biological Chemistry | volume = 273 | issue = 49 | pages = 33035–41 | date = Dec 1998 | pmid = 9830057 | doi = 10.1074/jbc.273.49.33035 | doi-access = free }}</ref>
* [[Grb2]],<ref name = pmid9830057>{{cite journal | vauthors = Karoor V, Wang L, Wang HY, Malbon CC | title = Insulin stimulates sequestration of beta-adrenergic receptors and enhanced association of beta-adrenergic receptors with Grb2 via tyrosine 350 | journal = The Journal of Biological Chemistry | volume = 273 | issue = 49 | pages = 33035–41 | date = Dec 1998 | pmid = 9830057 | doi = 10.1074/jbc.273.49.33035 | doi-access = free }}</ref>
* [[SNX27]]<ref name = pmid21602791>{{cite journal | vauthors = Temkin P, Lauffer B, Jäger S, Cimermancic P, Krogan NJ, von Zastrow M | title = SNX27 mediates retromer tubule entry and endosome-to-plasma membrane trafficking of signalling receptors | journal = Nature Cell Biology | volume = 13 | issue = 6 | pages = 715–21 | date = Jun 2011 | pmid = 21602791 | pmc = 3113693 | doi = 10.1038/ncb2252 }}</ref> and
* [[SNX27]]<ref name = pmid21602791>{{cite journal | vauthors = Temkin P, Lauffer B, Jäger S, Cimermancic P, Krogan NJ, von Zastrow M | title = SNX27 mediates retromer tubule entry and endosome-to-plasma membrane trafficking of signalling receptors | journal = Nature Cell Biology | volume = 13 | issue = 6 | pages = 715–21 | date = Jun 2011 | pmid = 21602791 | pmc = 3113693 | doi = 10.1038/ncb2252 }}</ref> and
* [[Sodium-hydrogen antiporter 3 regulator 1|SLC9A3R1]].<ref name = pmid11882663>{{cite journal | vauthors = Karthikeyan S, Leung T, Ladias JA | title = Structural determinants of the Na+/H+ exchanger regulatory factor interaction with the beta 2 adrenergic and platelet-derived growth factor receptors | journal = The Journal of Biological Chemistry | volume = 277 | issue = 21 | pages = 18973–8 | date = May 2002 | pmid = 11882663 | doi = 10.1074/jbc.M201507200 | doi-access = free }}</ref><ref name = pmid9671706>{{cite journal | vauthors = Hall RA, Ostedgaard LS, Premont RT, Blitzer JT, Rahman N, Welsh MJ, Lefkowitz RJ | title = A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 15 | pages = 8496–501 | date = Jul 1998 | pmid = 9671706 | pmc = 21104 | doi = 10.1073/pnas.95.15.8496 |bibcode = 1998PNAS...95.8496H }}</ref><ref name = pmid9560162>{{cite journal | vauthors = Hall RA, Premont RT, Chow CW, Blitzer JT, Pitcher JA, Claing A, Stoffel RH, Barak LS, Shenolikar S, Weinman EJ, Grinstein S, Lefkowitz RJ | title = The beta2-adrenergic receptor interacts with the Na+/H+-exchanger regulatory factor to control Na+/H+ exchange | journal = Nature | volume = 392 | issue = 6676 | pages = 626–30 | date = Apr 1998 | pmid = 9560162 | doi = 10.1038/33458 |bibcode = 1998Natur.392..626H }}</ref>
* [[Sodium-hydrogen antiporter 3 regulator 1|SLC9A3R1]].<ref name = pmid11882663>{{cite journal | vauthors = Karthikeyan S, Leung T, Ladias JA | title = Structural determinants of the Na+/H+ exchanger regulatory factor interaction with the beta 2 adrenergic and platelet-derived growth factor receptors | journal = The Journal of Biological Chemistry | volume = 277 | issue = 21 | pages = 18973–8 | date = May 2002 | pmid = 11882663 | doi = 10.1074/jbc.M201507200 | doi-access = free }}</ref><ref name = pmid9671706>{{cite journal | vauthors = Hall RA, Ostedgaard LS, Premont RT, Blitzer JT, Rahman N, Welsh MJ, Lefkowitz RJ | title = A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 15 | pages = 8496–501 | date = Jul 1998 | pmid = 9671706 | pmc = 21104 | doi = 10.1073/pnas.95.15.8496 |bibcode = 1998PNAS...95.8496H | doi-access = free }}</ref><ref name = pmid9560162>{{cite journal | vauthors = Hall RA, Premont RT, Chow CW, Blitzer JT, Pitcher JA, Claing A, Stoffel RH, Barak LS, Shenolikar S, Weinman EJ, Grinstein S, Lefkowitz RJ | title = The beta2-adrenergic receptor interacts with the Na+/H+-exchanger regulatory factor to control Na+/H+ exchange | journal = Nature | volume = 392 | issue = 6676 | pages = 626–30 | date = Apr 1998 | pmid = 9560162 | doi = 10.1038/33458 |bibcode = 1998Natur.392..626H | s2cid = 4422540 }}</ref>
{{Div col end}}
{{Div col end}}


Line 187: Line 194:
== Further reading ==
== Further reading ==
{{refbegin|32em}}
{{refbegin|32em}}
* {{cite journal | vauthors = Frielle T, Caron MG, Lefkowitz RJ | title = Properties of the beta 1- and beta 2-adrenergic receptor subtypes revealed by molecular cloning | journal = Clinical Chemistry | volume = 35 | issue = 5 | pages = 721–5 | date = May 1989 | pmid = 2541947 | doi = 10.1093/clinchem/35.5.721}}
* {{cite journal | vauthors = Frielle T, Caron MG, Lefkowitz RJ | title = Properties of the beta 1- and beta 2-adrenergic receptor subtypes revealed by molecular cloning | journal = Clinical Chemistry | volume = 35 | issue = 5 | pages = 721–5 | date = May 1989 | pmid = 2541947 | doi = 10.1093/clinchem/35.5.721| doi-access = free }}
* {{cite journal | vauthors = Taylor DR, Kennedy MA | title = Genetic variation of the beta(2)-adrenoceptor: its functional and clinical importance in bronchial asthma | journal = American Journal of Pharmacogenomics | volume = 1 | issue = 3 | pages = 165–74 | year = 2002 | pmid = 12083965 | doi = 10.2165/00129785-200101030-00002 }}
* {{cite journal | vauthors = Taylor DR, Kennedy MA | title = Genetic variation of the beta(2)-adrenoceptor: its functional and clinical importance in bronchial asthma | journal = American Journal of Pharmacogenomics | volume = 1 | issue = 3 | pages = 165–74 | year = 2002 | pmid = 12083965 | doi = 10.2165/00129785-200101030-00002 | s2cid = 116089602 }}
* {{cite book | vauthors = Thibonnier M, Coles P, Thibonnier A, Shoham M | title = Molecular pharmacology and modeling of vasopressin receptors | journal = Progress in Brain Research | volume = 139 | issue = | pages = 179–96 | year = 2002 | pmid = 12436935 | doi = 10.1016/S0079-6123(02)39016-2 | isbn = 9780444509826 }}
* {{cite book | vauthors = Thibonnier M, Coles P, Thibonnier A, Shoham M | chapter = Chapter 14 Molecular pharmacology and modeling of vasopressin receptors | title = Vasopressin and Oxytocin: From Genes to Clinical Applications | series = Progress in Brain Research | volume = 139 | pages = 179–96 | year = 2002 | pmid = 12436935 | doi = 10.1016/S0079-6123(02)39016-2 | isbn = 9780444509826 }}
* {{cite journal | vauthors = Ge D, Huang J, He J, Li B, Duan X, Chen R, Gu D | title = beta2-Adrenergic receptor gene variations associated with stage-2 hypertension in northern Han Chinese | journal = Annals of Human Genetics | volume = 69 | issue = Pt 1 | pages = 36–44 | date = Jan 2005 | pmid = 15638826 | doi = 10.1046/j.1529-8817.2003.00093.x }}
* {{cite journal | vauthors = Ge D, Huang J, He J, Li B, Duan X, Chen R, Gu D | title = beta2-Adrenergic receptor gene variations associated with stage-2 hypertension in northern Han Chinese | journal = Annals of Human Genetics | volume = 69 | issue = Pt 1 | pages = 36–44 | date = Jan 2005 | pmid = 15638826 | doi = 10.1046/j.1529-8817.2003.00093.x | s2cid = 6485276 | doi-access = free }}
* {{cite journal | vauthors = Muszkat M | title = Interethnic differences in drug response: the contribution of genetic variability in beta adrenergic receptor and cytochrome P4502C9 | journal = Clinical Pharmacology and Therapeutics | volume = 82 | issue = 2 | pages = 215–8 | date = Aug 2007 | pmid = 17329986 | doi = 10.1038/sj.clpt.6100142 }}
* {{cite journal | vauthors = Muszkat M | title = Interethnic differences in drug response: the contribution of genetic variability in beta adrenergic receptor and cytochrome P4502C9 | journal = Clinical Pharmacology and Therapeutics | volume = 82 | issue = 2 | pages = 215–8 | date = Aug 2007 | pmid = 17329986 | doi = 10.1038/sj.clpt.6100142 | s2cid = 10381767 }}
* {{cite journal | vauthors = von Zastrow M, Kobilka BK | title = Ligand-regulated internalization and recycling of human beta 2-adrenergic receptors between the plasma membrane and endosomes containing transferrin receptors | journal = The Journal of Biological Chemistry | volume = 267 | issue = 5 | pages = 3530–8 | date = Feb 1992 | pmid = 1371121 | doi = }}
* {{cite journal | vauthors = von Zastrow M, Kobilka BK | title = Ligand-regulated internalization and recycling of human beta 2-adrenergic receptors between the plasma membrane and endosomes containing transferrin receptors | journal = The Journal of Biological Chemistry | volume = 267 | issue = 5 | pages = 3530–8 | date = Feb 1992 | doi = 10.1016/S0021-9258(19)50762-1 | pmid = 1371121 | doi-access = free }}
* {{cite journal | vauthors = Gope R, Gope ML, Thorson A, Christensen M, Smyrk T, Chun M, Alvarez L, Wildrick DM, Boman BM | title = Genetic changes at the beta-2-adrenergic receptor locus on chromosome 5 in human colorectal carcinomas | journal = Anticancer Research | volume = 11 | issue = 6 | pages = 2047–50 | year = 1992 | pmid = 1663718 | doi = }}
* {{cite journal | vauthors = Gope R, Gope ML, Thorson A, Christensen M, Smyrk T, Chun M, Alvarez L, Wildrick DM, Boman BM | title = Genetic changes at the beta-2-adrenergic receptor locus on chromosome 5 in human colorectal carcinomas | journal = Anticancer Research | volume = 11 | issue = 6 | pages = 2047–50 | year = 1992 | pmid = 1663718 }}
* {{cite journal | vauthors = Bouvier M, Guilbault N, Bonin H | title = Phorbol-ester-induced phosphorylation of the beta 2-adrenergic receptor decreases its coupling to Gs | journal = FEBS Letters | volume = 279 | issue = 2 | pages = 243–8 | date = Feb 1991 | pmid = 1848190 | doi = 10.1016/0014-5793(91)80159-Z }}
* {{cite journal | vauthors = Bouvier M, Guilbault N, Bonin H | title = Phorbol-ester-induced phosphorylation of the beta 2-adrenergic receptor decreases its coupling to Gs | journal = FEBS Letters | volume = 279 | issue = 2 | pages = 243–8 | date = Feb 1991 | pmid = 1848190 | doi = 10.1016/0014-5793(91)80159-Z | s2cid = 28959833 | doi-access = free | bibcode = 1991FEBSL.279..243B }}
* {{cite journal | vauthors = Yang-Feng TL, Xue FY, Zhong WW, Cotecchia S, Frielle T, Caron MG, Lefkowitz RJ, Francke U | title = Chromosomal organization of adrenergic receptor genes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 4 | pages = 1516–20 | date = Feb 1990 | pmid = 2154750 | pmc = 53506 | doi = 10.1073/pnas.87.4.1516 | bibcode = 1990PNAS...87.1516Y }}
* {{cite journal | vauthors = Yang-Feng TL, Xue FY, Zhong WW, Cotecchia S, Frielle T, Caron MG, Lefkowitz RJ, Francke U | title = Chromosomal organization of adrenergic receptor genes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 4 | pages = 1516–20 | date = Feb 1990 | pmid = 2154750 | pmc = 53506 | doi = 10.1073/pnas.87.4.1516 | bibcode = 1990PNAS...87.1516Y | doi-access = free }}
* {{cite journal | vauthors = Hui KK, Yu JL | title = Effects of protein kinase inhibitor, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, on beta-2 adrenergic receptor activation and desensitization in intact human lymphocytes | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 249 | issue = 2 | pages = 492–8 | date = May 1989 | pmid = 2470898 | doi = }}
* {{cite journal | vauthors = Hui KK, Yu JL | title = Effects of protein kinase inhibitor, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, on beta-2 adrenergic receptor activation and desensitization in intact human lymphocytes | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 249 | issue = 2 | pages = 492–8 | date = May 1989 | pmid = 2470898 }}
* {{cite journal | vauthors = Hen R, Axel R, Obici S | title = Activation of the beta 2-adrenergic receptor promotes growth and differentiation in thyroid cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 12 | pages = 4785–8 | date = Jun 1989 | pmid = 2471981 | pmc = 287358 | doi = 10.1073/pnas.86.12.4785 | bibcode = 1989PNAS...86.4785H }}
* {{cite journal | vauthors = Hen R, Axel R, Obici S | title = Activation of the beta 2-adrenergic receptor promotes growth and differentiation in thyroid cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 12 | pages = 4785–8 | date = Jun 1989 | pmid = 2471981 | pmc = 287358 | doi = 10.1073/pnas.86.12.4785 | bibcode = 1989PNAS...86.4785H | doi-access = free }}
* {{cite journal | vauthors = O'Dowd BF, Hnatowich M, Caron MG, Lefkowitz RJ, Bouvier M | title = Palmitoylation of the human beta 2-adrenergic receptor. Mutation of Cys341 in the carboxyl tail leads to an uncoupled nonpalmitoylated form of the receptor | journal = The Journal of Biological Chemistry | volume = 264 | issue = 13 | pages = 7564–9 | date = May 1989 | pmid = 2540197 | doi = }}
* {{cite journal | vauthors = O'Dowd BF, Hnatowich M, Caron MG, Lefkowitz RJ, Bouvier M | title = Palmitoylation of the human beta 2-adrenergic receptor. Mutation of Cys341 in the carboxyl tail leads to an uncoupled nonpalmitoylated form of the receptor | journal = The Journal of Biological Chemistry | volume = 264 | issue = 13 | pages = 7564–9 | date = May 1989 | doi = 10.1016/S0021-9258(18)83271-9 | pmid = 2540197 | doi-access = free }}
* {{cite journal | vauthors = Bristow MR, Hershberger RE, Port JD, Minobe W, Rasmussen R | title = Beta 1- and beta 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium | journal = Molecular Pharmacology | volume = 35 | issue = 3 | pages = 295–303 | date = Mar 1989 | pmid = 2564629 | doi = }}
* {{cite journal | vauthors = Bristow MR, Hershberger RE, Port JD, Minobe W, Rasmussen R | title = Beta 1- and beta 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium | journal = Molecular Pharmacology | volume = 35 | issue = 3 | pages = 295–303 | date = Mar 1989 | pmid = 2564629 }}
* {{cite journal | vauthors = Emorine LJ, Marullo S, Delavier-Klutchko C, Kaveri SV, Durieu-Trautmann O, Strosberg AD | title = Structure of the gene for human beta 2-adrenergic receptor: expression and promoter characterization | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 84 | issue = 20 | pages = 6995–9 | date = Oct 1987 | pmid = 2823249 | pmc = 299215 | doi = 10.1073/pnas.84.20.6995 | bibcode = 1987PNAS...84.6995E }}
* {{cite journal | vauthors = Emorine LJ, Marullo S, Delavier-Klutchko C, Kaveri SV, Durieu-Trautmann O, Strosberg AD | title = Structure of the gene for human beta 2-adrenergic receptor: expression and promoter characterization | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 84 | issue = 20 | pages = 6995–9 | date = Oct 1987 | pmid = 2823249 | pmc = 299215 | doi = 10.1073/pnas.84.20.6995 | bibcode = 1987PNAS...84.6995E | doi-access = free }}
* {{cite journal | vauthors = Chung FZ, Wang CD, Potter PC, Venter JC, Fraser CM | title = Site-directed mutagenesis and continuous expression of human beta-adrenergic receptors. Identification of a conserved aspartate residue involved in agonist binding and receptor activation | journal = The Journal of Biological Chemistry | volume = 263 | issue = 9 | pages = 4052–5 | date = Mar 1988 | pmid = 2831218 | doi = }}
* {{cite journal | vauthors = Chung FZ, Wang CD, Potter PC, Venter JC, Fraser CM | title = Site-directed mutagenesis and continuous expression of human beta-adrenergic receptors. Identification of a conserved aspartate residue involved in agonist binding and receptor activation | journal = The Journal of Biological Chemistry | volume = 263 | issue = 9 | pages = 4052–5 | date = Mar 1988 | doi = 10.1016/S0021-9258(18)68888-X | pmid = 2831218 | doi-access = free }}
* {{cite journal | vauthors = Yang SD, Fong YL, Benovic JL, Sibley DR, Caron MG, Lefkowitz RJ | title = Dephosphorylation of the beta 2-adrenergic receptor and rhodopsin by latent phosphatase 2 | journal = The Journal of Biological Chemistry | volume = 263 | issue = 18 | pages = 8856–8 | date = Jun 1988 | pmid = 2837466 | doi = }}
* {{cite journal | vauthors = Yang SD, Fong YL, Benovic JL, Sibley DR, Caron MG, Lefkowitz RJ | title = Dephosphorylation of the beta 2-adrenergic receptor and rhodopsin by latent phosphatase 2 | journal = The Journal of Biological Chemistry | volume = 263 | issue = 18 | pages = 8856–8 | date = Jun 1988 | doi = 10.1016/S0021-9258(18)68386-3 | pmid = 2837466 | doi-access = free }}
* {{cite journal | vauthors = Kobilka BK, Dixon RA, Frielle T, Dohlman HG, Bolanowski MA, Sigal IS, Yang-Feng TL, Francke U, Caron MG, Lefkowitz RJ | title = cDNA for the human beta 2-adrenergic receptor: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 84 | issue = 1 | pages = 46–50 | date = Jan 1987 | pmid = 3025863 | pmc = 304138 | doi = 10.1073/pnas.84.1.46 | bibcode = 1987PNAS...84...46K }}
* {{cite journal | vauthors = Kobilka BK, Dixon RA, Frielle T, Dohlman HG, Bolanowski MA, Sigal IS, Yang-Feng TL, Francke U, Caron MG, Lefkowitz RJ | title = cDNA for the human beta 2-adrenergic receptor: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 84 | issue = 1 | pages = 46–50 | date = Jan 1987 | pmid = 3025863 | pmc = 304138 | doi = 10.1073/pnas.84.1.46 | bibcode = 1987PNAS...84...46K | doi-access = free }}
* {{cite journal | vauthors = Chung FZ, Lentes KU, Gocayne J, Fitzgerald M, Robinson D, Kerlavage AR, Fraser CM, Venter JC | title = Cloning and sequence analysis of the human brain beta-adrenergic receptor. Evolutionary relationship to rodent and avian beta-receptors and porcine muscarinic receptors | journal = FEBS Letters | volume = 211 | issue = 2 | pages = 200–6 | date = Jan 1987 | pmid = 3026848 | doi = 10.1016/0014-5793(87)81436-9 }}
* {{cite journal | vauthors = Chung FZ, Lentes KU, Gocayne J, Fitzgerald M, Robinson D, Kerlavage AR, Fraser CM, Venter JC | title = Cloning and sequence analysis of the human brain beta-adrenergic receptor. Evolutionary relationship to rodent and avian beta-receptors and porcine muscarinic receptors | journal = FEBS Letters | volume = 211 | issue = 2 | pages = 200–6 | date = Jan 1987 | pmid = 3026848 | doi = 10.1016/0014-5793(87)81436-9 | s2cid = 221452296 | doi-access = | bibcode = 1987FEBSL.211..200C }}
{{refend}}
{{refend}}


== External links ==
== External links ==
* {{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2189 | title = &beta;<sub>2</sub>-adrenoceptor | accessdate = | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | pages = | archiveurl = | archivedate = }}
* {{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2189 | title = β<sub>2</sub>-adrenoceptor | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | access-date = 2008-11-25 | archive-date = 2015-01-12 | archive-url = https://web.archive.org/web/20150112084733/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2189 | url-status = dead }}
* {{UCSC gene info|ADRB2}}
* {{UCSC gene info|ADRB2}}
* {{PDBe-KB2|P07550| Beta-2 adrenergic receptor}}
* {{PDBe-KB2|P07550| Beta-2 adrenergic receptor}}

Latest revision as of 14:42, 6 November 2024

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

[edit]

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

[edit]

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

[edit]

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

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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

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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

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Eye

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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

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Other

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  • 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

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Agonists

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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

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Tocolytic agents

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β2 agonists used for other purposes

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Antagonists

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(Beta blockers)

* denotes selective antagonist to the receptor.

Allosteric modulators

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

Interactions

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

See also

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References

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Further reading

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