Send to

Choose Destination
Mol Pharmacol. 2018 Jul 6. pii: mol.118.112524. doi: 10.1124/mol.118.112524. [Epub ahead of print]

Small molecule G protein-coupled receptor kinase inhibitors attenuate GRK2-mediated desensitization of vasoconstrictor-induced arterial contractions.

Author information

Univeristy of Leicester.
University of Leicester.
University of Michigan.
University of Leicester;


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.


Blood vessels; Calcium; G protein-coupled receptor kinases (GPKs); Hypertension; Vascular smooth muscle

Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center