Molecular Pharmacology, Vol 14, 1079-1091, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

Effects of Insulin, Methoxamine, and Calcium on Glycogen Synthase in Rat Adipocytes

¹ University of Virginia School of Medicine, Department of Pharmacology, Charlottesville, Virginia 22903

Inactivation of glycogen synthase by methoxamine was not associated with changes in cyclic AMP and was abolished by the alpha adrenergic antagonists phentolamine, phenoxybenzamine, and dihydroergotamine. The effect of methoxamine was not reversed by atropine or the beta adrenergic antagonists propranolol or practolol. Methoxamine decreased the percentage of glycogen synthase I activity that had been increased by incubating cells with 100 microunits/ml insulin; however, an effect of insulin was observed at the highest concentration of methoxamine tested (100 µM). The effect of 10 µM methoxamine was not overcome by 25 milliunits/ml of insulin. The inactivation of glycogen synthase by methoxamine was abolished by incubating cells in calcium-free medium containing 1 mM EGTA, and the effect of methoxamine was restored by adding calcium. Incubation of cells with the divalent cation ionophore A23187 decreased the percentage of glycogen synthase I activity in the presence of, but not the absence of calcium. When A23187 and methoxamine were added together, no further decrease in the percentage of glycogen synthase I activity was observed below that produced by either agent alone. The activation of glycogen synthase by insulin was not diminished by incubating cells in calcium-free medium plus 1 mM EGTA. An effect of insulin on glycogen synthase was observed even in the presence of A23187. The results indicate that the increase in the percentage of glycogen synthase I activity due to insulin is independent of extracellular calcium. Alpha adrenergic receptor stimulation may lead to a decrease in the percentage of glycogen synthase I activity by increasing the concentration of cytosolic calcium. If the activation of glycogen synthase involves calcium, presumably insulin would act by decreasing cytosolic calcium since the effects of insulin on glycogen synthase are opposite to those of methoxamine and A23187.

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