Mechanisms of catecholamine actions on liver carbohydrate metabolism.
Epinephrine rapidly activates phosphorylase in hepatocytes, mainly by a mechanism(s) involving alpha-adrenergic and not beta-adrenergic receptors. The alpha-adrenergic mechanism does not involve accumulation of cAMP or activation of cAMP-dependent protein kinase. It is impaired when hepatocytes are depleted of calcium by EGTA treatment and is rapidly restored by readdition of calcium. Basal phosphorylase is also lowered by calcium deficiency and rapidly increased by calcium but not other divalent cations. The divalent cation ioniphore A23187 increases phosphorylase a levels in hepatocytes in a calcium-dependent manner. Calcium deficiency does not modify the effects of glucagon, cAMP, or beta-adrenergic activation on phosphorylase. Activation of alpha-adrenergic receptors rapidly increases 45Ca fluxes in hepatocytes. Glucagon produces similar effects, but supraphysiological concentrations are required. The hypothesis is advanced that alpha-adrenergic activation of phosphorylase involves alterations in cell calcium such that there is an increase in cytosolic Ca2+ concentration leading to increased phosphorylase kinase activity. Epinephrine induces greater cAMP accumulation in calcium-depleted cells than in normal cells. The effect is mediated by alpha-adrenergic and not beta-adrenergic receptors. Calcium deficiency also cuases cAMP accumulation in hepatocytes incubated with phenylephrine but does not modify the responses of the cells to isoproterenol, glucagon, or cAMP. Low concentrations of calcium rapidly reverse alpha-adrenergic receptor-mediated cAMP accumulation in calcium-depleted cells. The hypothesis is advanced that calcium normally exerts an inhibitory effect on a linkage between alpha-adrenergic receptors and adenylate cyclase in hepatocytes.
D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology / Q000502:physiology; D050260:Carbohydrate Metabolism; D002395:Catecholamines / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004837:Epinephrine / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008112:Liver Glycogen / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D006005:Phosphorylases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D013565:Sympatholytics / Q000494:pharmacology
D002395:Catecholamines; D008112:Liver Glycogen; D013565:Sympatholytics; D010656:Phenylephrine; D000001:Calcimycin; D000242:Cyclic AMP; D006005:Phosphorylases; D011494:Protein Kinases; D002118:Calcium; D004837:Epinephrine