Desch, Matthias and Sigl, Katja and Hieke, Bernhard and Salb, Katharina and Kees, Frieder and Bernhard, Dominik and Jochim, Angela and Spiessberger, Beate and Hoecherl, Klaus and Feil, Robert and Feil, Susanne and Lukowski, Robert and Wegener, Joerg W. and Hofmann, Franz and Schlossmann, Jens (2010) IRAG determines nitric oxide- and atrial natriuretic peptide-mediated smooth muscle relaxation. CARDIOVASCULAR RESEARCH, 86 (3). pp. 496-505. ISSN 0008-6363,
Full text not available from this repository. (Request a copy)Abstract
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. IRAG deletion prevented stable interaction of IP(3) receptor type I (IP(3)RI) with cGKI beta determined by cGMP affinity chromatography. Confocal microscopy in vascular smooth muscle cells (VSMCs) showed that localization of cGKI beta and cGKI alpha 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 cGKI beta in smooth muscle from cGKI beta-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. These findings indicate that signalling of cGKI beta 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | DEPENDENT PROTEIN-KINASE; MYOSIN-BINDING SUBUNIT; CGMP KINASE; BLOOD-PRESSURE; I-ALPHA; SIGNALING COMPLEX; LEUCINE-ZIPPER; SUBSTRATE IRAG; PKGI-ALPHA; CELLS; Inositol trisphosphate receptor-associated cGMP kinase I substrate; Nitric oxide; Atrial natriuretic peptide; cGMP-dependent protein kinase I; Smooth muscle relaxation |
| Subjects: | 500 Science > 570 Life sciences 600 Technology > 615 Pharmacy |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie Chemistry and Pharmacy > Institute of Pharmacy > Pharmacology and Toxicology (Prof. Schlossmann, formerly Prof. Seifert) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 28 Jul 2020 09:07 |
| Last Modified: | 28 Jul 2020 09:07 |
| URI: | https://pred.uni-regensburg.de/id/eprint/24585 |
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