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- Title
IRAG is essential for relaxation of receptor-triggered smooth muscle contraction by cGMP kinase.
- Authors
Geuselhorunger, Angela; Werner, Matthias; Sigi, Katja; Smital, Petra; Wörner, René; Acheo, Linda; Stieber, Juliane; Weinmeister, Pascal; Feil, Robert; Feil, Susanne; Wegener, Jörg; Hofmann, Franz; Schlossmann, Jens
- 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 (IP3RI)-associated protein (IRAG), which decreases hormone-induced IP3-dependent Ca2+ 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-IP3RI interaction and resulted in hypomorphic IRAGΔ12/Δ12 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 IRAGΔ12/Δ12 mice were not relaxed by cGMP, while cAMP-mediated relaxation was unperturbed. Norepinephrine-induced increases in [Ca2+]i were not decreased by cGMP in aortic smooth muscle cells from IRAGΔ12/Delta;12 mice. In contrast, cGMP-induced relaxation of potassium-induced smooth muscle contraction was not abolished in IRAGΔ12/Delta;12 mice. We conclude that cGMP-dependent relaxation of hormone receptor-triggered smooth muscle contraction essentially depends on the interaction of cGKI-IRAG with IP3RI.
- Subjects
PROTEIN kinases; SMOOTH muscle; GASTROINTESTINAL motility; MICE; MUSCLE contraction; HORMONE receptors
- Publication
EMBO Journal, 2004, Vol 23, Issue 21, p4222
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1038/sj.emboj.7600440