3':5'-cyclic guanosine monophosphate (cGMP) potentiates the inositol 1,4,5-trisphosphate-evoked Ca2+ release in guinea-pig hepatocytes

The effect of cGMP on noradrenaline-induced intracellular Ca2+ mobilization was investigated in whole-cell voltage-clamped guinea-pig hepatocytes. Treatment of the cells with 8-Br-cGMP (1-500 mu M) resulted in an increase in the sensitivity of the cells to noradrenaline and to inositol 1,4,5-trisphosphate (InsP(3)) photo-released from caged InsP,. The positive effect of 8-Br-cGMP on the Ca2+ release evoked by Ca2+-mobilizing agonists or InsP(3) was blocked by a protein kinase G (PKG; cGMP-dependent protein kinase) inhibitor, the RP-8-(4-chlorophenylthio)guanosine 3':5'- monophosphorothioate. 8-Br-cGMP affected neither the basal InsP(3) concentration nor the noradrenaline-induced production of InsP(3). In permeabilized hepatocytes, the dose-response curve for InsP(3)-induced Ca2+ release was shifted to the left in the presence of 8-Br-cGMP. Furthermore, the treatment with 8-Br-cGMP did not affect the Ca2+ content of the InsP(3)-sensitive Ca2+ stores. These results indicate that intracellular cGMP potentiates the noradrenaline-induced Ca2+ response by enhancing Ca2+ release from the intracellular Ca2+ stores. We suggest that cGMP increases the apparent affinity of InsP(3) receptors for InsP(3) in guinea-pig hepatocytes probably by phosphorylation via the activation of PKG.