IRAG is essential for relaxation of receptor-triggered smooth muscle contraction by cGMP kinase |
| |
Authors: | Geiselhöringer Angela Werner Matthias Sigl Katja Smital Petra Wörner René Acheo Linda Stieber Juliane Weinmeister Pascal Feil Robert Feil Susanne Wegener Jörg Hofmann Franz Schlossmann Jens |
| |
Institution: | 1.Institut für Pharmakologie und Toxikologie, Technische Universität München, München, Germany |
| |
Abstract: | Signalling by cGMP-dependent protein kinase type I (cGKI) relaxes various smooth muscles modulating thereby vascular tone and gastrointestinal motility. cGKI-dependent relaxation is possibly mediated by phosphorylation of the inositol 1,4,5-trisphosphate receptor I (IP(3)RI)-associated protein (IRAG), which decreases hormone-induced IP(3)-dependent Ca(2+) release. We show now that the targeted deletion of exon 12 of IRAG coding for the N-terminus of the coiled-coil domain disrupted in vivo the IRAG-IP(3)RI interaction and resulted in hypomorphic IRAG(Delta12/Delta12) mice. These mice had a dilated gastrointestinal tract and a disturbed gastrointestinal motility. Carbachol- and phenylephrine-contracted smooth muscle strips from colon and aorta, respectively, of IRAG(Delta12/Delta12) mice were not relaxed by cGMP, while cAMP-mediated relaxation was unperturbed. Norepinephrine-induced increases in Ca(2+)](i) were not decreased by cGMP in aortic smooth muscle cells from IRAG(Delta12/Delta12) mice. In contrast, cGMP-induced relaxation of potassium-induced smooth muscle contraction was not abolished in IRAG(Delta12/Delta12) mice. We conclude that cGMP-dependent relaxation of hormone receptor-triggered smooth muscle contraction essentially depends on the interaction of cGKI-IRAG with IP(3)RI. |
| |
Keywords: | cGKI IP3R IRAG relaxation smooth muscle |
本文献已被 PubMed 等数据库收录! |
|