IRAG determines nitric oxide- and atrial natriuretic peptide-mediated smooth muscle relaxation - PubMed
- ️Fri Jan 01 2010
. 2010 Jun 1;86(3):496-505.
doi: 10.1093/cvr/cvq008. Epub 2010 Jan 15.
Katja Sigl, Bernhard Hieke, Katharina Salb, Frieder Kees, Dominik Bernhard, Angela Jochim, Beate Spiessberger, Klaus Höcherl, Robert Feil, Susanne Feil, Robert Lukowski, Jörg W Wegener, Franz Hofmann, Jens Schlossmann
Affiliations
- PMID: 20080989
- DOI: 10.1093/cvr/cvq008
IRAG determines nitric oxide- and atrial natriuretic peptide-mediated smooth muscle relaxation
Matthias Desch et al. Cardiovasc Res. 2010.
Abstract
Aims: Nitric oxide (NO) and atrial natriuretic peptide (ANP) signalling via cGMP controls smooth muscle tone. One important signalling pathway of cGMP-dependent protein kinase type I (cGKI) is mediated by IRAG (IP(3) receptor associated cGKI substrate) which is highly expressed in smooth muscle tissues. To elucidate the role of IRAG for NO- and ANP-mediated smooth muscle tone regulation, cGKI localization, and for its possible function in blood pressure adjustment, we generated IRAG-knockout mice by targeted deletion of exon 3.
Methods and results: IRAG deletion prevented stable interaction of IP(3) receptor type I (IP(3)RI) with cGKIbeta determined by cGMP affinity chromatography. Confocal microscopy in vascular smooth muscle cells (VSMCs) showed that localization of cGKIbeta and cGKIalpha did not change in absence of IRAG. NO-, ANP-, and cGMP-dependent relaxation of hormone-contracted aortic vessels and colon was significantly affected in IRAG-knockout mice. The suppression of cGMP-induced relaxation was not rescued by selective expression of cGKIbeta in smooth muscle from cGKIbeta-transgenic mice. NO-, ANP-, and cGMP-mediated inhibition of the hormone-induced increase in intracellular calcium concentration measured by Fura2 was suppressed in IRAG-deficient VSMC. Telemetric measurements revealed that IRAG-deficient animals exhibited normal basal tone, but were resistant to blood pressure reduction induced by lipopolysaccharide-treatment.
Conclusion: These findings indicate that signalling of cGKIbeta via IRAG is an essential functional part for regulation of smooth muscle tone and of intracellular calcium by NO (exogenously applicated or endogenously synthesized) and by ANP. IRAG signalling does not modulate basal tone but might be important for blood pressure regulation under pathophysiological conditions.
Similar articles
-
IRAG is essential for relaxation of receptor-triggered smooth muscle contraction by cGMP kinase.
Geiselhöringer A, Werner M, Sigl K, Smital P, Wörner R, Acheo L, Stieber J, Weinmeister P, Feil R, Feil S, Wegener J, Hofmann F, Schlossmann J. Geiselhöringer A, et al. EMBO J. 2004 Oct 27;23(21):4222-31. doi: 10.1038/sj.emboj.7600440. Epub 2004 Oct 14. EMBO J. 2004. PMID: 15483626 Free PMC article.
-
Distribution of IRAG and cGKI-isoforms in murine tissues.
Geiselhöringer A, Gaisa M, Hofmann F, Schlossmann J. Geiselhöringer A, et al. FEBS Lett. 2004 Sep 24;575(1-3):19-22. doi: 10.1016/j.febslet.2004.08.030. FEBS Lett. 2004. PMID: 15388327
-
Schlossmann J, Ammendola A, Ashman K, Zong X, Huber A, Neubauer G, Wang GX, Allescher HD, Korth M, Wilm M, Hofmann F, Ruth P. Schlossmann J, et al. Nature. 2000 Mar 9;404(6774):197-201. doi: 10.1038/35004606. Nature. 2000. PMID: 10724174
-
Molecular mechanism of cGMP-mediated smooth muscle relaxation.
Carvajal JA, Germain AM, Huidobro-Toro JP, Weiner CP. Carvajal JA, et al. J Cell Physiol. 2000 Sep;184(3):409-20. doi: 10.1002/1097-4652(200009)184:3<409::AID-JCP16>3.0.CO;2-K. J Cell Physiol. 2000. PMID: 10911373 Review.
-
cGMP regulated protein kinases (cGK).
Hofmann F, Bernhard D, Lukowski R, Weinmeister P. Hofmann F, et al. Handb Exp Pharmacol. 2009;(191):137-62. doi: 10.1007/978-3-540-68964-5_8. Handb Exp Pharmacol. 2009. PMID: 19089329 Review.
Cited by
-
The Golgi apparatus regulates cGMP-dependent protein kinase I compartmentation and proteolysis.
Kato S, Chen J, Cornog KH, Zhang H, Roberts JD Jr. Kato S, et al. Am J Physiol Cell Physiol. 2015 Jun 1;308(11):C944-58. doi: 10.1152/ajpcell.00199.2014. Epub 2015 Apr 8. Am J Physiol Cell Physiol. 2015. PMID: 25855081 Free PMC article.
-
Novel Functional Features of cGMP Substrate Proteins IRAG1 and IRAG2.
Prüschenk S, Majer M, Schlossmann J. Prüschenk S, et al. Int J Mol Sci. 2023 Jun 7;24(12):9837. doi: 10.3390/ijms24129837. Int J Mol Sci. 2023. PMID: 37372987 Free PMC article. Review.
-
IRAG1 Deficient Mice Develop PKG1β Dependent Pulmonary Hypertension.
Biswas S, Kojonazarov B, Hadzic S, Majer M, Bajraktari G, Novoyatleva T, Ghofrani HA, Grimminger F, Seeger W, Weissmann N, Schlossmann J, Schermuly RT. Biswas S, et al. Cells. 2020 Oct 13;9(10):2280. doi: 10.3390/cells9102280. Cells. 2020. PMID: 33066124 Free PMC article.
-
Nitric Oxide Signals Through IRAG to Inhibit TRPM4 Channels and Dilate Cerebral Arteries.
Ali S, Solano AS, Gonzales AL, Thakore P, Krishnan V, Yamasaki E, Earley S. Ali S, et al. Function (Oxf). 2021 Oct 9;2(6):zqab051. doi: 10.1093/function/zqab051. eCollection 2021. Function (Oxf). 2021. PMID: 34734188 Free PMC article.
-
Inositol trisphosphate receptors in smooth muscle cells.
Narayanan D, Adebiyi A, Jaggar JH. Narayanan D, et al. Am J Physiol Heart Circ Physiol. 2012 Jun 1;302(11):H2190-210. doi: 10.1152/ajpheart.01146.2011. Epub 2012 Mar 23. Am J Physiol Heart Circ Physiol. 2012. PMID: 22447942 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Molecular Biology Databases