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IRAG is essential for relaxation of receptor‐triggered smooth muscle contraction by cGMP kinase
Author(s) -
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
Publication year - 2004
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600440
Subject(s) - biology , contraction (grammar) , muscle contraction , microbiology and biotechnology , receptor , kinase , biophysics , anatomy , biochemistry , endocrinology
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 Δ12/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 IRAG Δ12/Δ12 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 Δ12/Δ12 mice. In contrast, cGMP‐induced relaxation of potassium‐induced smooth muscle contraction was not abolished in IRAG Δ12/Δ12 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.