Please use this identifier to cite or link to this item:
Title: Small molecule G protein-coupled receptor kinase inhibitors attenuate GRK2-mediated desensitization of vasoconstrictor-induced arterial contractions.
Authors: Rainbow, Richard D.
Brennan, Sean
Jackson, Robert
Beech, Alison J.
Bengreed, Amal
Waldschmidt, Helen V.
Tesmer, John J. G.
Challiss, R. A. John
Willets, Jonathon M.
First Published: 6-Jul-2018
Publisher: American Society for Pharmacology and Experimental Therapeutics (ASPET)
Citation: Molecular Pharmacology, 2018, 94 (3), pp. 1079-1091
Abstract: Vasoconstrictor-driven G protein-coupled receptor (GPCR)/phospholipase C (PLC) signalling increases intracellular Ca2+ concentration to mediate arterial contraction. To counteract vasoconstrictor-induced contraction, GPCR/PLC signalling can be desensitized by G protein-coupled receptor kinases (GRKs), with GRK2 playing a predominant role in isolated arterial smooth muscle cells. Here, we utilize an array of GRK2 inhibitors to assess their effects on the desensitization of UTP and angiotensin II-mediated arterial contractions. The effects of GRK2 inhibitors on the desensitization of UTP or angiotensin II (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. Pre-incubation with the GRK2 inhibitor paroxetine almost completely prevented desensitization of UTP- and attenuated desensitization of AngII-stimulated arterial contractions. In contrast, fluoxetine was ineffective. Pre-incubation 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+, whilst fluoxetine did not. In human uterine smooth muscle cells, paroxetine reversed GRK2-mediated histamine H1 receptor desensitization, but not GRK6-mediated oxytocin receptor desensitization. Utilising 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.
DOI Link: 10.1124/mol.118.112524
ISSN: 0026-895X
eISSN: 1521-0111
Embargo on file until: 1-Jan-10000
Version: Post-print
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2018, American Society for Pharmacology and Experimental Therapeutics (ASPET). Deposited with reference to the publisher’s open access archiving policy. (
Description: The file associated with this record is under embargo while permission to archive is sought from the publisher. The full text may be available through the publisher links provided above.
Appears in Collections:Published Articles, Dept. of Molecular and Cell Biology

Files in This Item:
File Description SizeFormat 
Rainbow et al-2018-Mol Pharmacol.pdfPost-review (final submitted author manuscript)6.26 MBAdobe PDFView/Open

Items in LRA are protected by copyright, with all rights reserved, unless otherwise indicated.