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|Title:||Small molecule G protein-coupled receptor kinase inhibitors attenuate GRK2-mediated desensitization of vasoconstrictor-induced arterial contractions.|
|Authors:||Rainbow, Richard D.|
Beech, Alison J.
Waldschmidt, Helen V.
Tesmer, John J. G.
Challiss, R. A. John
Willets, Jonathon M.
|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.|
|Embargo on file until:||1-Jan-10000|
|Rights:||Copyright © 2018, American Society for Pharmacology and Experimental Therapeutics (ASPET). Deposited with reference to the publisher’s open access archiving policy. (http://www.rioxx.net/licenses/all-rights-reserved)|
|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|
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|Rainbow et al-2018-Mol Pharmacol.pdf||Post-review (final submitted author manuscript)||6.26 MB||Adobe PDF||View/Open|
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