BIOMAT Database Logo BIOMAT Database Logo

Small-Molecule G Protein-Coupled Receptor Kinase Inhibitors Attenuate G Protein-Coupled Receptor Kinase 2-Mediated Desensitization of Vasoconstrictor-Induced Arterial Contractions. 2018

Richard D Rainbow, and Sean Brennan, and Robert Jackson, and Alison J Beech, and Amal Bengreed, and Helen V Waldschmidt, and John J G Tesmer, and R A John Challiss, and Jonathon M Willets
Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom (A.B., R.A.J.C., J.M.W.); Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield General Hospital, Leicester, United Kingdom (R.D.R., S.B., R.J., A.J.B.); Life Sciences Institute and Departments of Pharmacology, Biological Sciences, and Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan (H.V.W., J.J.G.T.); and Department of Biological Sciences, Purdue University, West Lafayette, Indiana (J.J.G.T.).

Vasoconstrictor-driven G protein-coupled receptor (GPCR)/phospholipase C (PLC) signaling increases intracellular Ca2+ concentration to mediate arterial contraction. To counteract vasoconstrictor-induced contraction, GPCR/PLC signaling can be desensitized by G protein-coupled receptor kinases (GRKs), with GRK2 playing a predominant role in isolated arterial smooth muscle cells. In this study, we use an array of GRK2 inhibitors to assess their effects on the desensitization of UTP and angiotensin II (AngII)-mediated arterial contractions. The effects of GRK2 inhibitors on the desensitization of UTP- or AngII-stimulated mesenteric third-order arterial contractions, and PLC activity in isolated mesenteric smooth muscle cells (MSMC), were determined using wire myography and Ca2+ imaging, respectively. Applying a stimulation protocol to cause receptor desensitization resulted in reductions in UTP- and AngII-stimulated arterial contractions. Preincubation with the GRK2 inhibitor paroxetine almost completely prevented desensitization of UTP- and attenuated desensitization of AngII-stimulated arterial contractions. In contrast, fluoxetine was ineffective. Preincubation with alternative GRK2 inhibitors (Takeda compound 101 or CCG224063) also attenuated the desensitization of UTP-mediated arterial contractile responses. In isolated MSMC, paroxetine, Takeda compound 101, and CCG224063 also attenuated the desensitization of UTP- and AngII-stimulated increases in Ca2+, whereas fluoxetine did not. In human uterine smooth muscle cells, paroxetine reversed GRK2-mediated histamine H1 receptor desensitization, but not GRK6-mediated oxytocin receptor desensitization. Utilizing various small-molecule GRK2 inhibitors, we confirm that GRK2 plays a central role in regulating vasoconstrictor-mediated arterial tone, highlighting a potentially novel strategy for blood pressure regulation through targeting GRK2 function.

UI MeSH Term Description Entries
D008297 Male Males
D008638 Mesenteric Arteries Arteries which arise from the abdominal aorta and distribute to most of the intestines. Arteries, Mesenteric,Artery, Mesenteric,Mesenteric Artery
D009131 Muscle, Smooth, Vascular The nonstriated involuntary muscle tissue of blood vessels. Vascular Smooth Muscle,Muscle, Vascular Smooth,Muscles, Vascular Smooth,Smooth Muscle, Vascular,Smooth Muscles, Vascular,Vascular Smooth Muscles
D002461 Cell Line, Transformed Eukaryotic cell line obtained in a quiescent or stationary phase which undergoes conversion to a state of unregulated growth in culture, resembling an in vitro tumor. It occurs spontaneously or through interaction with viruses, oncogenes, radiation, or drugs/chemicals. Transformed Cell Line,Cell Lines, Transformed,Transformed Cell Lines
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D014661 Vasoconstriction The physiological narrowing of BLOOD VESSELS by contraction of the VASCULAR SMOOTH MUSCLE. Vasoconstrictions
D014662 Vasoconstrictor Agents Drugs used to cause constriction of the blood vessels. Vasoactive Agonist,Vasoactive Agonists,Vasoconstrictor,Vasoconstrictor Agent,Vasoconstrictor Drug,Vasopressor Agent,Vasopressor Agents,Vasoconstrictor Drugs,Vasoconstrictors,Agent, Vasoconstrictor,Agent, Vasopressor,Agents, Vasoconstrictor,Agents, Vasopressor,Agonist, Vasoactive,Agonists, Vasoactive,Drug, Vasoconstrictor,Drugs, Vasoconstrictor
D017208 Rats, Wistar A strain of albino rat developed at the Wistar Institute that has spread widely at other institutions. This has markedly diluted the original strain. Wistar Rat,Rat, Wistar,Wistar Rats

Related Publications

Richard D Rainbow, and Sean Brennan, and Robert Jackson, and Alison J Beech, and Amal Bengreed, and Helen V Waldschmidt, and John J G Tesmer, and R A John Challiss, and Jonathon M Willets
G protein-coupled receptor kinase 2 is essential to enable vasoconstrictor-mediated arterial smooth muscle proliferation.
December 2021, Cellular signalling,
Richard D Rainbow, and Sean Brennan, and Robert Jackson, and Alison J Beech, and Amal Bengreed, and Helen V Waldschmidt, and John J G Tesmer, and R A John Challiss, and Jonathon M Willets
Monocyte chemoattractant protein-1-induced CCR2B receptor desensitization mediated by the G protein-coupled receptor kinase 2.
March 1998, Proceedings of the National Academy of Sciences of the United States of America,
Richard D Rainbow, and Sean Brennan, and Robert Jackson, and Alison J Beech, and Amal Bengreed, and Helen V Waldschmidt, and John J G Tesmer, and R A John Challiss, and Jonathon M Willets
G-protein-coupled receptor kinase 2-mediated desensitization of adiponectin receptor 1 in failing heart.
April 2015, Circulation,
Richard D Rainbow, and Sean Brennan, and Robert Jackson, and Alison J Beech, and Amal Bengreed, and Helen V Waldschmidt, and John J G Tesmer, and R A John Challiss, and Jonathon M Willets
Desensitization of vascular endothelin receptors by G protein-coupled receptor kinase 2.
February 2010, Cardiovascular research,
Richard D Rainbow, and Sean Brennan, and Robert Jackson, and Alison J Beech, and Amal Bengreed, and Helen V Waldschmidt, and John J G Tesmer, and R A John Challiss, and Jonathon M Willets
Desensitization and internalization of endothelin receptor A: impact of G protein-coupled receptor kinase 2 (GRK2)-mediated phosphorylation.
November 2013, The Journal of biological chemistry,
Richard D Rainbow, and Sean Brennan, and Robert Jackson, and Alison J Beech, and Amal Bengreed, and Helen V Waldschmidt, and John J G Tesmer, and R A John Challiss, and Jonathon M Willets
G protein-coupled receptor kinase mediates desensitization of norepinephrine-induced Ca2+ channel inhibition.
March 1996, Neuron,
Richard D Rainbow, and Sean Brennan, and Robert Jackson, and Alison J Beech, and Amal Bengreed, and Helen V Waldschmidt, and John J G Tesmer, and R A John Challiss, and Jonathon M Willets
G protein-coupled receptor kinase-mediated desensitization of metabotropic glutamate receptor 1A protects against cell death.
December 2000, The Journal of biological chemistry,
Richard D Rainbow, and Sean Brennan, and Robert Jackson, and Alison J Beech, and Amal Bengreed, and Helen V Waldschmidt, and John J G Tesmer, and R A John Challiss, and Jonathon M Willets
G protein coupled receptor kinase-2 upregulation causes κ-opioid receptor desensitization in diabetic heart.
January 2017, Biochemical and biophysical research communications,
Richard D Rainbow, and Sean Brennan, and Robert Jackson, and Alison J Beech, and Amal Bengreed, and Helen V Waldschmidt, and John J G Tesmer, and R A John Challiss, and Jonathon M Willets
Selective reduction in A2 adenosine receptor desensitization following antisense-induced suppression of G protein-coupled receptor kinase 2 expression.
November 1999, Journal of neurochemistry,
Richard D Rainbow, and Sean Brennan, and Robert Jackson, and Alison J Beech, and Amal Bengreed, and Helen V Waldschmidt, and John J G Tesmer, and R A John Challiss, and Jonathon M Willets
Molecular mechanism of selectivity among G protein-coupled receptor kinase 2 inhibitors.
August 2011, Molecular pharmacology,
Copied contents to your clipboard!