InsP3R-associated cGMP kinase substrate (IRAG) is essential for nitric oxide-induced inhibition of calcium signaling in human colonic smooth muscle

doi:10.1074/jbc.M313365200

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Papers In Press, published online ahead of print January 18, 2004
J. Biol. Chem, 10.1074/jbc.M313365200
Submitted on December 8, 2003
Revised on January 14, 2004
Accepted on January 17, 2004

InsP₃R-associated cGMP kinase substrate (IRAG) is essential for nitric oxide-induced inhibition of calcium signaling in human colonic smooth muscle

Ralph M. Fritsch, Dieter Saur, Manfred Kurjak, Daniela Oesterle, Jens Schlossmann, Angela Geiselhoringer, Franz Hofmann, and Hans-Dieter Allescher

Internal Medicine II, Technische Universitat Munchen, Munchen 81675

Corresponding Author: ralph.fritsch{at}lrz.tum.de

Nitric oxide (NO)-mediated relaxation of colonic smooth muscle is crucial for the maintenance of human gut function. The molecular mechanisms of NO-dependent smooth muscle relaxation involve cyclic GMP-mediated inhibition of store-dependent calcium signaling. Recently, IRAG (inositol 1,4,5-trisphosphate (InsP₃)-associated cGMP kinase substrate)has been characterized as a novel target molecule of cGMP-dependent protein kinase (cGKI) mediating NO/cGMP-dependent inhibition of inositol 1,4,5-trisphosphate(InsP₃)-dependent calcium release in transfected COS-cells. The aim of the present study was to characterize IRAG expression and its functional role in NO-dependent signaling in human colonic smooth muscle. RT-PCR revealed IRAG mRNA expression in human colon, rectum and in cultured colonic smooth muscle cells. In cultured colonic smooth muscle cells, Bradykinin elicited InsP₃-dependent calcium transients that were repeatable and independent of extracellular calcium. The NO-donor sodium nitroprusside (SNP) and the specific cGK-activator 8-pCPT-cGMP significantly inhibited BK-induced increase in intracelllar calcium. Cells transfected with antisense oligonucleotides raised against IRAG (IRAG-AS)showed strongly decreased IRAG protein expression. In these cells, SNP and 8-pCPT-cGMP both failed to modulate BK-induced calcium transients. Thus, endogenous IRAG appears to be essentially involved in the NO/cGK-dependent inhibition of InsP₃-dependent Ca²⁺-signaling in colonic smooth muscl

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