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Signaling of NO/cGMP via IRAG
BMC Pharmacology volume 7, Article number: S49 (2007)
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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Schlossmann, J. Signaling of NO/cGMP via IRAG. BMC Pharmacol 7, S49 (2007). https://doi.org/10.1186/1471-2210-7-S1-S49
- Smooth Muscle
- Platelet Aggregation
- Thrombus Formation