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J. Biol. Chem., Vol. 279, Issue 13, 12551-12559, March 26, 2004

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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 Geiselhöringer¶, Franz Hofmann¶, and Hans-Dieter Allescher

From the Department of Internal Medicine II and the ^¶Institut für Pharmakologie und Toxikologie der Technischen Universitat Munchen, 81675 Munchen, Germany

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-trisphophate receptor-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. Reverse transcriptase-PCR revealed IRAG mRNA expression in human colon, rectum, and cultured colonic smooth muscle cells. In cultured human colonic smooth muscle cells, bradykinin (BK) elicited InsP₃-dependent calcium transients that were repeatable and independent of extracellular calcium. The NO donor sodium nitroprusside and the specific cGK activator 8-(4-chlorophenylthio)guanosine-3',5'-cyclic-monophosphate (8-pCPT-cGMP) significantly inhibited BK-induced increase in intracellular calcium. Cells transfected with antisense oligonucleotides raised against IRAG (IRAG-AS) showed strongly decreased IRAG protein expression. In these cells, sodium nitroprusside 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 muscle.

Received for publication, December 8, 2003 , and in revised form, January 14, 2004.

^* This work was supported by the Deutsche Forschungsgemeinschaft Grant SFB 391 C5. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Klinikum rechts der Isar, II, Medizinische Klinik, Technische Universitat Muenchen, Ismaninger Strasse 22, 81675 Munchen, Germany. Tel.: 0049-89-4140-2458; Fax: 0049-89-4140-4808; E-mail: ralph.fritsch{at}lrz.tum.de.

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