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

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 (IP 3 RI)‐associated protein (IRAG), which decreases hormone‐induced IP 3 ‐dependent Ca 2+ 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–IP 3 RI interaction and resulted in hypomorphic IRAG Δ12/Δ12 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 Δ12/Δ12 mice were not relaxed by cGMP, while cAMP‐mediated relaxation was unperturbed. Norepinephrine‐induced increases in [Ca 2+ ] i were not decreased by cGMP in aortic smooth muscle cells from IRAG Δ12/Δ12 mice. In contrast, cGMP‐induced relaxation of potassium‐induced smooth muscle contraction was not abolished in IRAG Δ12/Δ12 mice. We conclude that cGMP‐dependent relaxation of hormone receptor‐triggered smooth muscle contraction essentially depends on the interaction of cGKI–IRAG with IP 3 RI.