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Signaling of NO/cGMP via IRAG

Signaling by NO/cGMP/cGMP-dependent kinase I (cGKI) is important for a variety of physiological functions comprising relaxation of smooth muscle and inhibition of platelet aggregation. An important pathway of this signaling cascade includes the inositol 1,4,5-trisphosphate receptor I (IP3RI) associated protein cGMP kinase substrate (IRAG). This protein interacts in a trimeric macrocomplex with cGKIβ and the IP3RI. To get insight into the physiological function of IRAG two different mice strains were generated by targeted deletion: (1) IRAGΔ12/Δ12 with an exon 12 deletion disrupting the IRAG/IP3RI interaction. (2) IRAG-/- with an exon 3 deletion generating an IRAG knockout mutant.

Analysis of IRAGΔ12/Δ12 platelet aggregation in vitro using collagen and thrombin as agonists and Fura2 calcium measurements revealed that IP3RI/IRAG interaction is essential for NO/cGMP signaling mediating inhibition of platelet aggregation. Furthermore, it was shown that IP3RI/IRAG interaction is essential for the NO-dependent prevention of thrombus formation.

Relaxation of hormone-contracted aortic and longitudinal colonic smooth muscle by cGMP was abolished in IRAGΔ12/Δ12 mice and IRAG knockout mice indicating an essential role of IRAG for NO/cGMP-dependent smooth muscle relaxation. The vascular function of IRAG was underlined by a lack of NO-dependent blood pressure reduction in IRAGΔ12/Δ12 mice. These studies suggest that cGKI/IRAG/IP3RI is an essential signaling pathway modulating cardiovascular functions.

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Correspondence to Jens Schlossmann.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Schlossmann, J. Signaling of NO/cGMP via IRAG. BMC Pharmacol 7 (Suppl 1), S49 (2007).

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