IRAG is essential for relaxation of receptor-triggered smooth muscle contraction by cGMP kinase

被引：92

作者：

Geiselhöringer, A ^{[1
]}

Werner, M ^{[1
]}

Sigl, K ^{[1
]}

Smital, P ^{[1
]}

Wörner, R ^{[1
]}

Acheo, L ^{[1
]}

Stieber, J ^{[1
]}

Weinmeister, P ^{[1
]}

Feil, R ^{[1
]}

Feil, S ^{[1
]}

Wegener, J ^{[1
]}

Hofmann, F ^{[1
]}

Schlossmann, J ^{[1
]}

机构：

[1] Tech Univ Munich, Inst Pharmakol & Toxikol, D-80802 Munich, Germany

来源：

EMBO JOURNAL | 2004年 / 23卷 / 21期

关键词：

cGKI; IP3R; IRAG; relaxation; smooth muscle;

D O I：

10.1038/sj.emboj.7600440

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 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 [Ca2+](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 IP3RI.

引用

页码：4222 / 4231

页数：10

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