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J. Biol. Chem., Vol. 279, Issue 7, 5146-5151, February 13, 2004

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Modulation of Ca²⁺ Sensitivity by Cyclic Nucleotides in Smooth Muscle from Protein Kinase G-deficient Mice^*

Johan Bonnevier, Reinhard Fässler, Andrew P. Somlyo¶, Avril V. Somlyo¶, and Anders Arner||

From the Department of Physiological Sciences, Martinsried, Munich 82152, Germany, Max Planck Institute of Biochemistry, Department of Molecular Medicine, Munich 82152, Germany, and ^¶Department of Molecular Physiology and Biological Physics, University Virginia, Charlottesville, Virginia 22908-0736

The cGMP-dependent protein kinase (PKG) is the main mediator of nitric oxide-induced relaxation of smooth muscle. Although this pathway is well established, the cellular action of PKG, nitric oxide, and cGMP is complex and not fully understood. A cross-talk between the cGMP-PKG and other pathways (e.g. cAMP-protein kinase A) seems to exist. We have explored cGMP- and cAMP-dependent relaxation of smooth muscle using PKG-deficient mice (cGKI–/–). In intact ileum strips of wild type mice (cGKI+/+), 8-Br-cGMP inhibited the sustained phase of carbachol contractions by 80%. The initial peak was less inhibited (30%). This relaxation was associated with a reduction in intracellular [Ca²⁺] and decreased Ca²⁺ sensitivity. Contractions of cGKI–/– ileum were not influenced by 8-Br-cGMP. EC₅₀ for 8-Br-cGMP for PKG was estimated to be 10 nM. PKG-independent relaxation by 8-Br-cGMP had an EC₅₀ of 10 µM. Relaxation by cAMP (50% at 100 µM), Ca²⁺ sensitivity of force, and force potentiation by GTPS were similar in cGKI+/+ and cGKI–/– tissues. The results show that PKG is the main target for cGMP-induced relaxation in intestinal smooth muscle. cGMP desensitize the contractile system to Ca²⁺ via PKG. PKG-independent pathways are activated at 1000-fold higher cGMP concentrations. Relaxation by cAMP can occur independently of PKG. Long term deficiency of PKG does not lead to an apparent up-regulation of the cAMP-dependent pathways or changes in Ca²⁺ sensitivity.

Received for publication, June 19, 2003 , and in revised form, October 14, 2003.

^* This study was supported by grants from the Swedish Medical Research Council (04x-8268) (to A. A.), The Crafoord Foundation and the Medical Faculty, Lund University (National Institutes of Health Grant PO1 HL19242) (to A. V. S.) and (NIH PO1 HL48807) (to A. P. S.), and Fonds der Chemichen Industrie (to R. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| Present address and to whom correspondence should be addressed: Dept Physiological Sciences, Lund University, BMC F11, SE-221 84 Lund, Sweden. Tel.: 46-46-222-7758; Fax: 46-46-222-7765; E-mail: Anders.Arner{at}mphy.lu.se.

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