Small-Molecule G Protein-Coupled Receptor Kinase Inhibitors Attenuate G Protein-Coupled Receptor Kinase 2-Mediated Desensitization of Vasoconstrictor-Induced Arterial Contractions
| Autor: | Richard D. Rainbow, Jonathon M. Willets, John J.G. Tesmer, R. A. John Challiss, Robert Jackson, Sean Brennan, Helen V. Waldschmidt, Amal Bengreed, Alison J. Beech |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Vascular smooth muscle G-Protein-Coupled Receptor Kinase 2 Histamine H1 receptor 030204 cardiovascular system & hematology Pharmacology Muscle Smooth Vascular 03 medical and health sciences 0302 clinical medicine Animals Humans Vasoconstrictor Agents Rats Wistar Receptor Protein Kinase Inhibitors G protein-coupled receptor Cell Line Transformed G protein-coupled receptor kinase biology Phospholipase C Dose-Response Relationship Drug Chemistry Beta adrenergic receptor kinase Articles Angiotensin II Mesenteric Arteries Rats 030104 developmental biology Vasoconstriction biology.protein Molecular Medicine |
| Zdroj: | Molecular pharmacology. 94(3) |
| ISSN: | 1521-0111 |
| Popis: | Vasoconstrictor-driven G protein–coupled receptor (GPCR)/phospholipase C (PLC) signaling increases intracellular Ca(2+) 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 Ca(2+) 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 Ca(2+), whereas fluoxetine did not. In human uterine smooth muscle cells, paroxetine reversed GRK2-mediated histamine H(1) 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. |
| Databáze: | OpenAIRE |
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