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NEUROREGULATION AND MOTILITY

Calcium-dependent and calcium-independent inhibition of contraction by cGMP/cGKI in intestinal smooth muscle

Institut für Pharmakologie und Toxikologie, Technische Universität München, Munich, Germany

Submitted March 11, 2009 ; accepted in final form July 17, 2009

cGMP-dependent protein kinase I (cGKI) induces relaxation of smooth muscle via several pathways that include inhibition of intracellular Ca²⁺ signaling and/or involve activation of myosin phosphatase. In the present study, we investigated these mechanisms comparatively in colon and jejunum longitudinal smooth muscle from mice. In simultaneous recordings from colon muscle, 8-bromo-cGMP (8-Br-cGMP) reduced both carbachol-induced tension and carbachol-induced increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i). These effects of 8-Br-cGMP were absent in colon from mice carrying a mutated inositol-1,4,5 trisphosphate receptor I-associated G kinase substrate (IRAG) gene or lacking cGKI. However, in jejunum, 8-Br-cGMP reduced carbachol-induced tension but did not change corresponding [Ca²⁺]_i signals. This setting was also observed in jejunum from mice carrying a mutated IRAG gene, whereas no response to 8-Br-cGMP was observed in jejunum from mice lacking cGKI. After inhibition of phosphatase activity by calyculin A, 8-Br-cGMP did not relax jejunum but still relaxed colon muscle. In Western blot analysis, 8-Br-cGMP reduced the signal for phosphorylated MYPT-1 in carbachol-stimulated jejunum but not in colon. These results suggest that cGMP/cGKI signaling differentially inhibits contraction in the muscles investigated: in jejunum, inhibition is performed without changing [Ca²⁺]_i and is dependent on phosphatase activity, whereas in colon, inhibition is mediated by inhibition of [Ca²⁺]_i signals.

inositol-1,4,5 trisphosphate receptor I-associated G kinase substrate; myosin phosphatase targeting subunit 1; guanosine 3',5'-cyclic monophosphate-dependent protein kinase I; colon; jejunum