Evidence indicating that the glucagon‐induced increase in cytoplasmic free Ca2+ concentration in hepatocytes is mediated by an increase in cyclic AMP concentration

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Abstract
The mechanism whereby glucagon causes an increase in the concentration of cytoplasmic free Ca2+, [Ca2+]c, in isolated hepatocytes has been investigated. There have been proposals of cyclic‐AMP‐dependent and cyclic‐AMP‐independent mechanisms. In this work, the inactivation of pyruvate kinase was used as an indicator of increases in the activity of cyclic‐AMP‐dependent protein kinase, A‐kinase. [Ca2+]c was measured using the fluorescent probe indo‐1. The decrease in activity of pyruvate kinase caused by an increase in [Ca2+]c alone, i. e. mediated by mechanisms not involving cyclic AMP and exemplified by the effect of vasopressin, was of minimal significance under the conditions of the enzyme assay. Studies of the effects of a wide range of glucagon concentrations indicate that any increase in [Ca2+]c caused by glucagon was always associated with a decrease in pyruvate kinase activity. A similar relationship was obtained if glucagon‐receptor occupancy was circumvented by using the 8‐bromo‐derivative of cyclic AMP to activate the A‐kinase. It was also found that the cyclic AMP phosphodiesterase inhibitor isobutylmethylxanthine could potentiate the ability of glucagon to increase [Ca2+]c: no such potentiation was observed when vasopressin was used to raise [Ca2+]c. Together these data indicate that an increase in cyclic AMP concentration, sufficiently great to activate A‐kinase, is a mechanism that mediates the glucagon‐induced increase in [Ca2+]c.