Relaxation of vascular smooth muscle by the cGMP-kinase substrate IRAG
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KeywordsVascular Smooth Muscle Inositol Mutant Mouse Hind Limb Vascular Tone
Intracellular signalling by NO/cGMP-dependent protein kinase type I (cGKI) relaxes smooth muscles thereby modulating e.g. vascular tone. An important mediator of this signalling cascade is the inositol 1,4,5,-trisphosphate receptor I (IP3 RI) associated protein cGMP kinase substrate (IRAG). This protein forms a trimeric complex together with the cGMP kinase Iβ and the IP3 RI. Recently, it was shown that the relaxation of hormone-contracted aortic smooth muscle by cGMP was abolished in IRAG Δ12/Δ12 mutant mice with a disrupted IRAG-IP3 RI interaction site . Now we investigated whether IRAG might regulate the vascular tone in small vessels. NO-mediated relaxation of isolated arteria tibialis was nearly absent in the IRAG mutant. Moreover, the relaxing effect of IRAG on NO-mediated dilation of resistance vessels in perfused hind limbs of mutant mice was abolished.
To analyze the in vivio function of IRAG/IP3 RI interaction, we finally recorded blood pressure in conscious, freely moving animals via implanted radiotelemetric devices. After application of NO-donors blood pressure decrease was clearly diminished in IRAGΔ12/Δ12 mutants compared to control mice.
These data suggest that IRAG is essential for NO/cGMP-dependent relaxation of vascular smooth muscle.
- 1.Geiselhoringer A, Werner M, Sigl K, Smital P, Worner R, Acheo L, Stieber J, Weinmeister P, Feil R, Feil S, Wegener J, Hofmann F, Schlossmann J: IRAG is essential for relaxation of receptor-triggered smooth muscle contraction by cGMP kinase. EMBO J. 2007, 23: 4222-4231. 10.1038/sj.emboj.7600440.CrossRefGoogle Scholar
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