Interaction of Glucagon and Epinephrine in the Regulation of Adenosine 3′,5′-Monophosphate-Dependent Glycogenolysis in the Cultured Fetal Hepatocyte*

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Abstract
The hormonal control of glycogenolysis has been studied in 3-day-cultured fetal rat hepatocytes which contained stored glycogen. A single addition of 10 nM glucagon or 10 nM epinephrine produced an identical maximal glycogenolytic response, which developed within 4 h and ceased thereafter. The amount of glycogen degraded represented 60% of the stored glycogen or 95% of the newly synthesized glycogen after a 4-h preincubation period in the presence of [14C]glucose. The latter result demonstrates that both hormones interact on the same hepatocytes. Stimulation of glycogenolysis by glucagon or epinephrine was preceded by an accumulation of intracellular cAMP. From the decreasing order of potency of isoproterenol, epinephrine, norepinephrine, and phenylephrine to activate glycogenolysis, it can be concluded that the epinephrine effect is mainly mediated by β-adrenergic receptors. When glucagon and epinephrine were added simultaneously at maximal concentrations, the glycogenolytic effects were not additive. Moreover, when epinephrine was added 4 h after glucagon, it elicited a second glycogenolytic response, so that the amount of glycogen degraded represented 80% of the stored glycogen. At this stage, a second addition of glucagon was ineffective, and the extent of the glucagon-induced loss of response depended on the size of the first dose of hormone. Cell desensitization to glucagon for glycogenolysis was closely related to the associated response in cAMP production. This desensitization was found to be highly specific for glucagon and was accompanied by a defect in specific glucagon binding. The occurrence of a specific negative regulation of the response to glucagon explained how epinephrine was able to mobilize glycogen accumulated in the continued presence of glucagon during hepatocyte development in culture.

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