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m Anthony Appleyard moved page Beta adrenergic receptor kinase to G protein-coupled receptor kinase 2: Requested by RPremont at WP:RM/TR: Obsolete name for an enzyme/gene exchanged to accepted/official name, which already exists as a current #redirect
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'''Beta adrenergic receptor kinase''' (also referred to as '''βARK,''' '''BARK,''' or '''GRK2''') is a [[serine/threonine intracellular kinase]]. It is activated by [[cAMP-dependent protein kinase|PKA]], and its target is the [[beta adrenergic receptor]]. It is involved in one method by which a cell will desensitize itself from [[epinephrine]] overstimulation.<ref name="Pippig_1993">{{cite journal | vauthors = Pippig S, Andexinger S, Daniel K, Puzicha M, Caron MG, Lefkowitz RJ, Lohse MJ | title = Overexpression of beta-arrestin and beta-adrenergic receptor kinase augment desensitization of beta 2-adrenergic receptors | journal = J. Biol. Chem. | volume = 268 | issue = 5 | pages = 3201–8 | year = 1993 | pmid = 8381421 | doi = }}</ref><ref name="Pitcher_1992">{{cite journal | vauthors = Pitcher J, Lohse MJ, Codina J, Caron MG, Lefkowitz RJ | title = Desensitization of the isolated beta 2-adrenergic receptor by beta-adrenergic receptor kinase, cAMP-dependent protein kinase, and protein kinase C occurs via distinct molecular mechanisms | journal = Biochemistry | volume = 31 | issue = 12 | pages = 3193–7 | year = 1992 | pmid = 1348186 | doi = 10.1021/bi00127a021}}</ref>
'''G-protein-coupled receptor kinase 2''' (GRK2) is an [[enzyme]] that in humans is encoded by the ''ADRBK1'' [[gene]].<ref name="Benovic_1989">{{cite journal | vauthors = Benovic JL, DeBlasi A, Stone WC, Caron MG, Lefkowitz RJ | title = Beta-adrenergic receptor kinase: primary structure delineates a multigene family | journal = Science | volume = 246 | issue = 4927 | pages = 235–40 | year = 1989 | pmid = 2552582 | doi = 10.1126/science.2552582}}</ref> GRK2 was initially called '''Beta-adrenergic receptor kinase''' (βARK or βARK1), and is a member of the [[G protein-coupled receptor kinase]] subfamily of the Ser/Thr [[protein kinase]]s that is most highly similar to [[GRK3]](βARK2).<ref>{{cite journal | author=Benovic JL |title=Cloning, expression, and chromosomal localization of beta-adrenergic receptor kinase 2. A new member of the receptor kinase family |journal=J. Biol. Chem. |volume=266 |issue= 23 |pages= 14939–46 |year= 1991 |pmid= 1869533 |doi= |name-list-format=vanc| author2=Onorato JJ | author3=Arriza JL | display-authors=3 | last4=Stone | first4=WC | last5=Lohse | first5=M | last6=Jenkins | first6=NA | last7=Gilbert | first7=DJ | last8=Copeland | first8=NG | last9=Caron | first9=MG }}</ref>


==Activation==
== Functions ==
*'''Step 1:''' Upon stimulation of the beta adrenergic receptor by [[epinephrine]] (or [[norepinephrine]]), a conformational change change will occur within the Beta adrenergic receptor. This will provoke the receptor to activate its [[Heterotrimeric G protein|G protein]], causing the alpha subunit of the G protein to be released.
*'''Step 2:''' The alpha subunit of the G protein will stimulate the [[enzyme]] [[adenyl cyclase|adenylyl cyclase]] to make [[Cyclic adenosine monophosphate|cAMP]] (cyclic adenosine monophosphate) from ATP (adenosine triphosphate).
*'''Steps 3-6:''' cAMP will activate cAMP-dependent kinase (also known as protein kinase A or [[cAMP-dependent protein kinase|PKA]]), which will phosphorylate many proteins, one of which is βARK. Specifically, it will phosphorylate the serine and threonine residues on βARK.


G protein-coupled receptor kinases phosphorylate activated G protein-coupled receptors, which promotes the binding of an [[arrestin]] protein to the receptor. Arrestin binding to phosphorylated, active receptor prevents receptor stimulation of [[heterotrimeric G protein]] transducer proteins, blocking their cellular signaling and resulting in receptor [[desensitization (medicine) |desensitization]]. Arrestin binding also directs receptors to specific cellular [[Endocytosis |internalization pathways]], removing the receptors from the cell surface and also preventing additional activation. Arrestin binding to phosphorylated, active receptor also enables receptor signaling through arrestin partner proteins. Thus the GRK/arrestin system serves as a complex signaling switch for G protein-coupled receptors.<ref>{{cite journal |vauthors=Gurevich VV, Gurevich EV |title=GPCR Signaling Regulation: The Role of GRKs and Arrestins |journal=Front Pharmacol |volume=10 |issue= |pages= |year=2019 |pmid=30837883 |doi=10.3389/fphar.2019.00125 }}</ref>
[[File:Beta adrenergic receptor kinase.JPG|thumb|left|300px|Beta Adrenergic Receptor Kinase Activation Pathway.]]


GRK2 and the closely-related GRK3 phosphorylate receptors at sites that encourage arrestin-mediated receptor desensitization, internalization and trafficking rather than arrestin-mediated signaling (in contrast to [[GRK5]] and [[GRK6]], which have the opposite effect).<ref>{{cite journal |vauthors=Kim J, Ahn S, Ren XR, Whalen EJ, Reiter E, Wei H, Lefkowitz RJ |title=Functional antagonism of different G protein-coupled receptor kinases for beta-arrestin-mediated angiotensin II receptor signaling |journal=Proc Natl Acad Sci USA |volume=102 |issue=5 |pages=1442-1447 |year=2005 |pmid=15671181 |doi=10.1073/pnas.0409532102 }}</ref><ref>{{cite journal |vauthors=Ren XR, Reiter E, Ahn S, Kim J, Chen W, Lefkowitz RJ |title=Different G protein-coupled receptor kinases govern G protein and beta-arrestin-mediated signaling of V2 vasopressin receptor |journal=Proc Natl Acad Sci USA |volume=102 |issue=5 |pages=1448-1453 |year=2005 |pmid=15671180 |doi=10.1073/pnas.0409534102 }}</ref> This difference is one basis for pharmacological [[biased agonism]] (also called [[functional selectivity]]), where a drug binding to a receptor may bias that receptor’s signaling toward a particular subset of the actions stimulated by that receptor. <ref>{{cite journal |vauthors=Zidar DA, Violin JD, Whalen EJ, Lefkowitz RJ |title=Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands |journal=Proc Natl Acad Sci USA |volume=106 |issue=24 |pages=9649-9654 |year=2009 |pmid=19497875 |doi=10.1073/pnas.0904361106 }}</ref><ref>{{cite journal |vauthors=Choi M, Staus DP, Wingler LM, Ahn S, Pani B, Capel WD, Lefkowitz RJ |title=G protein-coupled receptor kinases (GRKs) orchestrate biased agonism at the β2-adrenergic receptor |journal=Sci Signal |volume=11 |issue=544 |pages= |year=2018 |pmid=30131371 |doi=10.1126/scisignal.aar7084 }}</ref>
*'''Step 7:''' βARK, itself a serine/threonine kinase, will then phosphorylate serine and threonine residues on the beta adrenergic receptor.
*'''Step 8:''' This will facilitate binding of beta-[[Arrestin|arrestins]] to the beta adrenergic receptor. The arrestins prevent additional stimulation by epinephrine by blocking reassociation of the G protein with the beta adrenergic receptor.<ref>{{Cite journal|last=Gurevich|first=V. V.|last2=Mushegian|first2=A.|last3=Tesmer|first3=J. J.|last4=Gurevich|first4=E. V.|date=August 26, 2011|title=G protein-coupled receptor kinases: more than just kinases and not only for GPCRs.|url=http://europepmc.org/abstract/med/21903131|journal=Pharmacology & therapeutics|volume=133|issue=1|pages=40–69|doi=10.1016/j.pharmthera.2011.08.001|issn=0163-7258|via=}}</ref>


GRK2 is expressed broadly in tissues, but generally at higher levels than the related GRK3.<ref>{{cite journal |vauthors=Arriza JL, Dawson TM, Simerly RB, Martin LJ, Caron MG, Snyder SH, Lefkowitz RJ |title=The G-protein-coupled receptor kinases beta ARK1 and beta ARK2 are widely distributed at synapses in rat brain |journal=J Neurosci |volume=12 |issue=10 |pages=4045-4055 |year=1992 |pmid=1403099 |doi= }}</ref> GRK2 was originally identified as a protein kinase that phosphorylated the β2-[[adrenergic receptor]], and has been most extensively studied as a regulator of adrenergic receptors (and other [[GPCR]]s) in the heart, where it has been proposed as a drug target to treat [[heart failure]].<ref name=”30701991”>{{cite journal |vauthors=Lieu M, Koch WJ |title=GRK2 and GRK5 as therapeutic targets and their role in maladaptive and pathological cardiac hypertrophy |journal=Expert Opin Ther Targets |volume=23 |issue=3 |pages=201-214 |year=2019 |pmid=30701991 |doi=10.1080/14728222.2019.1575363 }}</ref><ref>{{cite journal |vauthors=Murga C, Arcones AC, Cruces-Sande M, Briones AM, Salaices M, Mayor F Jr |title=G Protein-Coupled Receptor Kinase 2 (GRK2) as a Potential Therapeutic Target in Cardiovascular and Metabolic Diseases |journal= Front Pharmacol |volume=10 |issue= |pages=112 |year=2019 |pmid= 30837878 |doi=10.3389/fphar.2019.00112 }}</ref> Strategies to inhibit GRK2 include using small molecules (including [[Paroxetine]] and Compound-101) and using gene therapy approaches utilizing regulatory domains of GRK2 (particularly overexpressing the carboxy terminal [[pleckstrin homology domain |pleckstrin-homology (PH) domain]] that binds the [[G beta-gamma complex |G protein βγ-subunit complex]] and inhibits GRK2 activation (often called the “βARKct”), or just a peptide from this PH domain).<ref>{{cite journal |vauthors=Thal DM, Homan KT, Chen J, Wu EK, Hinkle PM, Huang ZM, Chuprun JK, Song J, Gao E, Cheung JY, Sklar LA, Koch WJ, Tesmer JJ |title=Paroxetine is a direct inhibitor of g protein-coupled receptor kinase 2 and increases myocardial contractility |journal=ACS Chem Biol |volume=7 |issue=11 |pages=1830-1839 |year=2012 |pmid=22882301 |doi=10.1021/cb3003013 }}</ref><ref name=”30701991” />
Therefore, βARK is a [[negative feedback]] enzyme that will prevent overstimulation of the β-adrenergic receptor.<ref name="Pippig_1993" /><ref name="Pitcher_1992" />


GRK2 and the related GRK3 can interact with heterotrimeric G protein subunits resulting from GPCR activation, both to be activated and to regulate G protein signaling pathways. GRK2 and GRK3 share a carboxyl terminal pleckstrin homology (PH) domain that binds to G protein βγ subunits, and GPCR activation of heterotrimeric G proteins releases this free βγ complex that binds to GRK2/3 to recruit these kinases to the cell membrane precisely at the location of the activated receptor, augmenting GRK activity to regulate the activated receptor.<ref name=”17084806”>{{cite journal |vauthors=Ribas C, Penela P, Murga C, Salcedo A, García-Hoz C, Jurado-Pueyo M, Aymerich I, Mayor F Jr |title=The G protein-coupled receptor kinase (GRK) interactome: role of GRKs in GPCR regulation and signaling |journal=Biochim Biophys Acta |volume=1768 |issue=4 |pages=913-922 |year=2007 |pmid=17084806 |doi=10.1016/j.bbamem.2006.09.019 }}</ref><ref name=”30837883”>{{cite journal |vauthors=Gurevich VV, Gurevich EV |title=GPCR Signaling Regulation: The Role of GRKs and Arrestins |journal=Front Pharmacol |volume=10 |issue= |pages= |year=2019 |pmid=30837883 |doi=10.3389/fphar.2019.00125 }}</ref> The amino terminal [[RGS protein |RGS-homology (RH) domain]] of GRK2 and GRK3 binds to heterotrimeric G protein subunits of the Gq family to reduce Gq signaling by sequestering active G proteins away from their effector proteins such as phospholipase C-beta; but the GRK2 and GRK3 RH domains are unable to function as GTPase-activating proteins (as do traditional [[RGS protein]]s) to turn off G protein signaling.<ref>{{cite journal |vauthors=Tesmer VM, Kawano T, Shankaranarayanan A, Kozasa T, Tesmer JJ |title=Snapshot of activated G proteins at the membrane: the Galphaq-GRK2-Gbetagamma complex |journal=Science |volume=310 |issue=5754 |pages=1686-1690 |year=2005 |pmid=16339447 |doi=10.1126/science.1118890 }}</ref>
==Other similar systems==
In the [[rhodopsin]] system, which regulates [[rod cell]] function in the [[retina]], [[rhodopsin kinase]] will phosphorylate serine and threonine residues on the rhodopsin receptor. Similarly to the βARK system, the phosphorylated rhodopsin residues will then bind to arrestins, resulting in receptor desensitization.


== Structure ==
== Interactions ==


GRK2 has been shown to [[Protein-protein interaction |interact]] with numerous protein partners,<ref>{{cite journal |vauthors=Hullmann J, Traynham CJ, Coleman RC, Koch WJ |title=The expanding GRK interactome: Implications in cardiovascular disease and potential for therapeutic development |journal=Pharmacol Res |volume=110 |issue= |pages=52-64 |year=2016 |pmid=27180008 |doi=10.1016/j.phrs.2016.05.008 }}</ref><ref name="pmid122277298">{{cite journal |vauthors=Evron T, Daigle TL, Caron MG |title=GRK2: multiple roles beyond G protein-coupled receptor desensitization |journal=Trends Pharmacol. Sci. |volume=33 |issue=3 |pages=154–64 |date=March 2012 |pmid=22277298 |doi=10.1016/j.tips.2011.12.003 |url= |pmc=3294176}}.</ref><ref>{{cite journal |vauthors=Penela P, Murga C, Ribas C, Lafarga V, Mayor F Jr |title=The complex G protein-coupled receptor kinase 2 (GRK2) interactome unveils new physiopathological targets |journal=Br J Pharmacol |volume=160 |issue=4 |pages=821-832 |year=2010 |pmid=20590581 |doi=10.1111/j.1476-5381.2010.00727.x }}</ref> including:
===Protein structure===
⚫
{{div col|colwidth=20em}}
The structure of βARK1 consists of a protein of 689 amino acids (79.7 kilodaltons) with a protein kinase catalytic domain that bears greatest sequence similarity to protein kinase C and the cyclic adenosine monophosphate (cyclic AMP)-dependent protein kinase.<ref name="Benovic_1989">{{cite journal | vauthors = Benovic JL, DeBlasi A, Stone WC, Caron MG, Lefkowitz RJ | title = Beta-adrenergic receptor kinase: primary structure delineates a multigene family | journal = Science | volume = 246 | issue = 4927 | pages = 235–40 | year = 1989 | pmid = 2552582 | doi = 10.1126/science.2552582}}</ref>
⚫
* [[G protein]] [[Beta-gamma complex |βγ complex]]<ref name = PMID21111235>{{cite journal | vauthors = Raveh A, Cooper A, Guy-David L, Reuveny E | title = Nonenzymatic rapid control of GIRK channel function by a G protein-coupled receptor kinase | journal = Cell | volume = 143 | issue = 5 | pages = 750–60 | date = November 2010 | pmid = 21111235 | doi = 10.1016/j.cell.2010.10.018 }}</ref>
⚫
* [[G protein]] [[GNAQ]] family members<ref name = pmid12885252>{{cite journal | vauthors = Day PW, Carman CV, Sterne-Marr R, Benovic JL, Wedegaertner PB | title = Differential interaction of GRK2 with members of the G alpha q family | journal = Biochemistry | volume = 42 | issue = 30 | pages = 9176–84 | date = August 2003 | pmid = 12885252 | doi = 10.1021/bi034442+ }}</ref><ref>{{cite journal |vauthors=Tesmer VM, Kawano T, Shankaranarayanan A, Kozasa T, Tesmer JJ |title=Snapshot of activated G proteins at the membrane: the Galphaq-GRK2-Gbetagamma complex |journal=Science |volume=310 |issue=5754 |pages=1686-1690 |year=2005 |pmid=16339447 |doi=10.1126/science.1118890 }}</ref>
⚫
* [[GIT1]] and [[GIT2]]<ref name = pmid10896954>{{cite journal | vauthors = Premont RT, Claing A, Vitale N, Perry SJ, Lefkowitz RJ | title = The GIT family of ADP-ribosylation factor GTPase-activating proteins. Functional diversity of GIT2 through alternative splicing | journal = J. Biol. Chem. | volume = 275 | issue = 29 | pages = 22373–80 | date = July 2000 | pmid = 10896954 | doi = 10.1074/jbc.275.29.22373}}</ref><ref name = pmid9826657>{{cite journal | vauthors = Premont RT, Claing A, Vitale N, Freeman JL, Pitcher JA, Patton WA, Moss J, Vaughan M, Lefkowitz RJ | title = beta2-Adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | issue = 24 | pages = 14082–7 | date = November 1998 | pmid = 9826657 | pmc = 24330 | doi = 10.1073/pnas.95.24.14082}}</ref>
⚫
* [[PDE6G]]<ref name = pmid12624098>{{cite journal | vauthors = Wan KF, Sambi BS, Tate R, Waters C, Pyne NJ | title = The inhibitory gamma subunit of the type 6 retinal cGMP phosphodiesterase functions to link c-Src and G-protein-coupled receptor kinase 2 in a signaling unit that regulates p42/p44 mitogen-activated protein kinase by epidermal growth factor | journal = J. Biol. Chem. | volume = 278 | issue = 20 | pages = 18658–63 | date = May 2003 | pmid = 12624098 | doi = 10.1074/jbc.M212103200 }}</ref>
⚫
* [[PRKCB1]]<ref name = pmid12679936>{{cite journal | vauthors = Yang XL, Zhang YL, Lai ZS, Xing FY, Liu YH | title = Pleckstrin homology domain of G protein-coupled receptor kinase-2 binds to PKC and affects the activity of PKC kinase | journal = World J. Gastroenterol. | volume = 9 | issue = 4 | pages = 800–3 | date = April 2003 | pmid = 12679936 | doi = }}</ref>
⚫
* [[Src (gene)|Src]]<ref name = pmid12624098/>


{{Div col end}}
===Gene structure===
The [[gene]] spans approximately 23 kilobases and is composed of 21 [[exons]] interrupted by 20 [[introns]]. Exon sizes range from 52 bases (exon 7) to over 1200 bases (exon 21), intron sizes from 68 bases (intron L) to 10.8 kilobases (intron A). The [[splice sites]] for donor and acceptor were in agreement with the canonical GT/AG rule. Functional regions of beta ARK are described with respect to their location within the exon-intron organization of the gene. [[Primer (molecular biology)|Primer]] extension and RNase protection assays suggest a major transcription start site approximately 246 bases upstream of the start ATG. Sequence analysis of the 5'-flanking/promoter region reveals many features characteristic of mammalian [[housekeeping genes]], i.e. the lack of a [[TATA box]], an absent or nonstandard positioned [[CAAT box]], high GC content, and the presence of Sp1-binding sites. The extraordinarily high GC content of the 5'-flanking region (> 80%) helps define this region as a CpG island that may be a principal regulator of beta ARK expression.<ref name="pmid8195124">{{cite journal | vauthors = Penn RB, Benovic JL | title = Structure of the human gene encoding the beta-adrenergic receptor kinase | journal = J. Biol. Chem. | volume = 269 | issue = 21 | pages = 14924–30 | year = 1994 | pmid = 8195124 | doi = }}</ref>

== Interactions ==
Beta adrenergic receptor kinase has been shown to [[Protein-protein interaction|interact]] with:
⚫
{{div col|colwidth=20em}}
⚫
* [[Beta-gamma complex]],<ref name = PMID21111235>{{cite journal | vauthors = Raveh A, Cooper A, Guy-David L, Reuveny E | title = Nonenzymatic rapid control of GIRK channel function by a G protein-coupled receptor kinase | journal = Cell | volume = 143 | issue = 5 | pages = 750–60 | date = November 2010 | pmid = 21111235 | doi = 10.1016/j.cell.2010.10.018 }}</ref>
* [[G protein]]
⚫
* [[GIT1]],<ref name = pmid10896954>{{cite journal | vauthors = Premont RT, Claing A, Vitale N, Perry SJ, Lefkowitz RJ | title = The GIT family of ADP-ribosylation factor GTPase-activating proteins. Functional diversity of GIT2 through alternative splicing | journal = J. Biol. Chem. | volume = 275 | issue = 29 | pages = 22373–80 | date = July 2000 | pmid = 10896954 | doi = 10.1074/jbc.275.29.22373}}</ref><ref name = pmid9826657>{{cite journal | vauthors = Premont RT, Claing A, Vitale N, Freeman JL, Pitcher JA, Patton WA, Moss J, Vaughan M, Lefkowitz RJ | title = beta2-Adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | issue = 24 | pages = 14082–7 | date = November 1998 | pmid = 9826657 | pmc = 24330 | doi = 10.1073/pnas.95.24.14082}}</ref>
⚫
* [[GNAQ]],<ref name = pmid12885252>{{cite journal | vauthors = Day PW, Carman CV, Sterne-Marr R, Benovic JL, Wedegaertner PB | title = Differential interaction of GRK2 with members of the G alpha q family | journal = Biochemistry | volume = 42 | issue = 30 | pages = 9176–84 | date = August 2003 | pmid = 12885252 | doi = 10.1021/bi034442+ }}</ref>
⚫
* [[PDE6G]],<ref name = pmid12624098>{{cite journal | vauthors = Wan KF, Sambi BS, Tate R, Waters C, Pyne NJ | title = The inhibitory gamma subunit of the type 6 retinal cGMP phosphodiesterase functions to link c-Src and G-protein-coupled receptor kinase 2 in a signaling unit that regulates p42/p44 mitogen-activated protein kinase by epidermal growth factor | journal = J. Biol. Chem. | volume = 278 | issue = 20 | pages = 18658–63 | date = May 2003 | pmid = 12624098 | doi = 10.1074/jbc.M212103200 }}</ref>
⚫
* [[PRKCB1]]<ref name = pmid12679936>{{cite journal | vauthors = Yang XL, Zhang YL, Lai ZS, Xing FY, Liu YH | title = Pleckstrin homology domain of G protein-coupled receptor kinase-2 binds to PKC and affects the activity of PKC kinase | journal = World J. Gastroenterol. | volume = 9 | issue = 4 | pages = 800–3 | date = April 2003 | pmid = 12679936 | doi = }}</ref> and
⚫
* [[Src (gene)|Src]].<ref name = pmid12624098/>
* [[Paroxetine]],<ref>Thal, D et al., (2012) [https://pubs.acs.org/doi/10.1021/cb3003013 Article in "The ACS Journal of Chemical Biology"] | doi = 10.1021/cb3003013]</ref>{{Div col end}}


== See also ==
== See also ==
⚫
* [[G protein-coupled receptor kinases]]
* [[G protein]]
* [[G protein]]
* [[desensitization (medicine)]]
⚫
* [[G protein-coupled receptor kinases]]
* [[arrestin]]
* [[Kinase]]
* [[Kinase]]


Revision as of 19:15, 4 June 2019

GRK2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesGRK2, BARK1, BETA-ARK1, ADRBK1, G protein-coupled receptor kinase 2
External IDsOMIM: 109635; MGI: 87940; HomoloGene: 1223; GeneCards: GRK2; OMA:GRK2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

156

110355

Ensembl

ENSG00000173020

ENSMUSG00000024858

UniProt

P25098

Q99MK8

RefSeq (mRNA)

NM_001619

NM_001290818
NM_130863

RefSeq (protein)

NP_001610

NP_001277747
NP_570933

Location (UCSC)Chr 11: 67.27 – 67.29 MbChr 19: 4.34 – 4.36 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

G-protein-coupled receptor kinase 2 (GRK2) is an enzyme that in humans is encoded by the ADRBK1 gene.[5] GRK2 was initially called Beta-adrenergic receptor kinase (βARK or βARK1), and is a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases that is most highly similar to GRK3(βARK2).[6]

Functions

G protein-coupled receptor kinases phosphorylate activated G protein-coupled receptors, which promotes the binding of an arrestin protein to the receptor. Arrestin binding to phosphorylated, active receptor prevents receptor stimulation of heterotrimeric G protein transducer proteins, blocking their cellular signaling and resulting in receptor desensitization. Arrestin binding also directs receptors to specific cellular internalization pathways, removing the receptors from the cell surface and also preventing additional activation. Arrestin binding to phosphorylated, active receptor also enables receptor signaling through arrestin partner proteins. Thus the GRK/arrestin system serves as a complex signaling switch for G protein-coupled receptors.[7]

GRK2 and the closely-related GRK3 phosphorylate receptors at sites that encourage arrestin-mediated receptor desensitization, internalization and trafficking rather than arrestin-mediated signaling (in contrast to GRK5 and GRK6, which have the opposite effect).[8][9] This difference is one basis for pharmacological biased agonism (also called functional selectivity), where a drug binding to a receptor may bias that receptor’s signaling toward a particular subset of the actions stimulated by that receptor. [10][11]

GRK2 is expressed broadly in tissues, but generally at higher levels than the related GRK3.[12] GRK2 was originally identified as a protein kinase that phosphorylated the β2-adrenergic receptor, and has been most extensively studied as a regulator of adrenergic receptors (and other GPCRs) in the heart, where it has been proposed as a drug target to treat heart failure.[13][14] Strategies to inhibit GRK2 include using small molecules (including Paroxetine and Compound-101) and using gene therapy approaches utilizing regulatory domains of GRK2 (particularly overexpressing the carboxy terminal pleckstrin-homology (PH) domain that binds the G protein βγ-subunit complex and inhibits GRK2 activation (often called the “βARKct”), or just a peptide from this PH domain).[15][13]

GRK2 and the related GRK3 can interact with heterotrimeric G protein subunits resulting from GPCR activation, both to be activated and to regulate G protein signaling pathways. GRK2 and GRK3 share a carboxyl terminal pleckstrin homology (PH) domain that binds to G protein βγ subunits, and GPCR activation of heterotrimeric G proteins releases this free βγ complex that binds to GRK2/3 to recruit these kinases to the cell membrane precisely at the location of the activated receptor, augmenting GRK activity to regulate the activated receptor.[16][17] The amino terminal RGS-homology (RH) domain of GRK2 and GRK3 binds to heterotrimeric G protein subunits of the Gq family to reduce Gq signaling by sequestering active G proteins away from their effector proteins such as phospholipase C-beta; but the GRK2 and GRK3 RH domains are unable to function as GTPase-activating proteins (as do traditional RGS proteins) to turn off G protein signaling.[18]

Interactions

GRK2 has been shown to interact with numerous protein partners,[19][20][21] including:

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000173020 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024858 – 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.
  5. ^ Benovic JL, DeBlasi A, Stone WC, Caron MG, Lefkowitz RJ (1989). "Beta-adrenergic receptor kinase: primary structure delineates a multigene family". Science. 246 (4927): 235–40. doi:10.1126/science.2552582. PMID 2552582.
  6. ^ Benovic JL; Onorato JJ; Arriza JL; et al. (1991). "Cloning, expression, and chromosomal localization of beta-adrenergic receptor kinase 2. A new member of the receptor kinase family". J. Biol. Chem. 266 (23): 14939–46. PMID 1869533. {{cite journal}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  7. ^ Gurevich VV, Gurevich EV (2019). "GPCR Signaling Regulation: The Role of GRKs and Arrestins". Front Pharmacol. 10. doi:10.3389/fphar.2019.00125. PMID 30837883.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  8. ^ Kim J, Ahn S, Ren XR, Whalen EJ, Reiter E, Wei H, Lefkowitz RJ (2005). "Functional antagonism of different G protein-coupled receptor kinases for beta-arrestin-mediated angiotensin II receptor signaling". Proc Natl Acad Sci USA. 102 (5): 1442–1447. doi:10.1073/pnas.0409532102. PMID 15671181.
  9. ^ Ren XR, Reiter E, Ahn S, Kim J, Chen W, Lefkowitz RJ (2005). "Different G protein-coupled receptor kinases govern G protein and beta-arrestin-mediated signaling of V2 vasopressin receptor". Proc Natl Acad Sci USA. 102 (5): 1448–1453. doi:10.1073/pnas.0409534102. PMID 15671180.
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External links

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