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Volume 271, Number 33, Issue of August 16, 1996 pp. 19817-19825
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Cyclic GMP Induces Oscillatory Calcium Signals in Rat Hepatocytes

(Received for publication, February 21, 1996, and in revised form, May, 22, 1996)

From the Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

The ability of guanosine-3,5-cyclic monophosphate (cGMP) to induce increases in the intracellular free calcium ion concentration ([Ca²⁺]_i) was studied at the single cell level in fura-2-loaded rat hepatocytes. Both 8-bromo-cGMP (Br-cGMP) and dibutyryl cGMP (db-cGMP) produced oscillatory [Ca²⁺]_i increases in hepatocytes. In addition, Br-cGMP increased the frequency of agonist-induced spiking or converted [Ca²⁺]_i oscillations into sustained nonoscillatory [Ca²⁺]_i responses. Addition of the nitric oxide donor sodium nitroprusside also produced oscillatory [Ca²⁺]_i increases similar to those generated by cGMP analogues. In the absence of extracellular Ca²⁺, cGMP-induced [Ca²⁺]_i responses were significantly reduced and mainly appeared as single transient [Ca²⁺]_i increases. The effects of cGMP analogues do not appear to be mediated by a secondary increase in cAMP or activation of cAMP-dependent protein kinase (PKA), since [Ca²⁺]_i responses to cGMP analogues were inhibited by the G-kinase inhibitor 8-bromoguanosine-3,5-cyclic monophosphorothioate (Rp-Br-cGMP[S]). Both Br-cGMP and db-cGMP also increased [Ca²⁺]_i in the presence of the PKA inhibitor 8-bromoadenosine-3,5-cyclic monophosphorothioate (Rp-Br-cAMP[S]) and when the cGMP-inhibitable cAMP phosphodiesterase activity was inhibited by pretreatment with siguazodan. Br-cGMP stimulated the Mn²⁺-induced quench of compartmentalized fura-2 in intact hepatocytes, indicating a site of action at the level of the Ca²⁺ stores. This locus was further supported by the finding that pretreatment of hepatocytes with Br-cGMP potentiated submaximal inositol 1,4,5-trisphosphate (InsP₃)-induced Mn²⁺ quench in subsequently permeabilized hepatocytes. db-cGMP also decreased PKA-mediated back phosphorylation of the hepatic type-1 InsP₃ receptor, indicating that G-kinase phosphorylates the InsP₃ receptor at sites targeted by PKA. These data indicate that phosphorylation of the hepatic InsP₃ receptor by G-kinase increases the sensitivity to InsP₃ for [Ca²⁺]_i release and is associated with the production of [Ca²⁺]_i oscillations in single rat hepatocytes.

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