Sodium fluoride acts as a stimulator and inhibitor of phosphoinositide hydrolysis in permeabilized rat hepatocytes.

To determine the effect of cyclic GMP and cyclic GMPdependent protein kinase, microsomes were preincubated for 10 min at 37°C with 100 pM-isobutylmethylxanthine, 1 pM-cyclic GMP alone, 16-138 p-units of cGMP-dependent protein kinase/ml alone or with the combination of these agents. Steady-state, ATP-dependent Ca? + accumulation into preparations sonicated with histamine amounted to 47 k 6 nmol/mg of protein (mean ~ s . E . M . , n=20) . Inclusion of 1 m~-p[NH]ppG resulted in a 44% decrease in Ca2+ accumulation (Fig. 1). Incubation of microsomes with cyclic GMP alone or cyclic GMP-dependent protein kinase alone did not alter the effect of p[NH]ppG. Incubation with cyclic GMP and cyclic GMP-dependent protein kinase (138 units/ ml) together appeared to overcome the effect of p[NH]ppG completely (Fig. 1). As detailed above, the decrease in Ca?+ accumulation caused by the combination of histamine and p[NH]ppG probably results from the opening of a receptor-mediated Ca2+ channel gated by a G-protein. The present results suggest that the Ca?+ channel can be closed by cyclic GMPdependent phosphorylation of one of its components, as yet unidentified. This interpretation is consistent with pharmacological findings that agents which increase cyclic GMP concentration cause a decrease in receptor-mediated Ca2 + influx [2-51.