Abstract
von Werder A, Mayr M, Schneider G, Oesterle D, Fritsch RM, Seidler B, Schlossmann J, Hofmann F, Schemann M, Allescher HD, Schmid RM, Saur D. Truncated IRAG variants modulate cGMP-mediated inhibition of human colonic smooth muscle cell contraction. Am J Physiol Cell Physiol 301: C1445-C1457, 2011. First published August 24, 2011; doi:10.1152/ajpcell.00304.2010.-Nitric oxide (NO) induces relaxation ...
Abstract
von Werder A, Mayr M, Schneider G, Oesterle D, Fritsch RM, Seidler B, Schlossmann J, Hofmann F, Schemann M, Allescher HD, Schmid RM, Saur D. Truncated IRAG variants modulate cGMP-mediated inhibition of human colonic smooth muscle cell contraction. Am J Physiol Cell Physiol 301: C1445-C1457, 2011. First published August 24, 2011; doi:10.1152/ajpcell.00304.2010.-Nitric oxide (NO) induces relaxation of colonic smooth muscle cells predominantly by cGMP/cGMP-dependent protein kinase I (cGKI)-induced phosphorylation of the inositol 1,4,5-trisphosphate receptor (IP3R)-associated cGMP kinase substrate (IRAG), to block store-dependent calcium signaling. In the present study we analyzed the structure and function of the human IRAG/MRVI1 gene. We describe four unique first exon variants transcribed from individual promoters in diverse human tissues. Tissue-specific alternative splicing with exon skipping and alternative splice donor and acceptor site usage further increases diversity of IRAG mRNA variants that encode for NH2- and COOH-terminally truncated proteins. At the functional level, COOH-terminally truncated IRAG variants lacking both the cGKI phosphorylation and the IP3RI interaction site counteract cGMP-mediated inhibition of calcium transients and relaxation of human colonic smooth muscle cells. Since COOH-terminally truncated IRAG mRNA isoforms are widely expressed in human tissues, our results point to an important role of IRAG variants as negative modulators of nitric oxide/cGKI-dependent signaling. The complexity of alternative splicing of the IRAG gene impressively demonstrates how posttranscriptional processing generates functionally distinct proteins from a single gene.
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