Molecular Pharmacology, Vol 18, 379-383, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

Independent Desensitization of -Adrenergic Receptor-Regulated Magnesium Transport and Cyclic AMP Accumulation

¹ Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106

We have previously shown that -adrenergic inhibition of Mg²⁺ transport in cultured S49 lymphoma cells is not mediated by cyclic AMP (Maguire, M. E., and J. J. Erdos. J. Biol. Chem. 255: 1030-1035 (1980). We now report that the rate of Mg²⁺ but not Ca²⁺ influx is decreased immediately upon the addition of (-)-isoproterenol and remains decreased at a constant rate for approximately 25 min in both wild-type and kinase^- clones in the continued presence of agonist. The rate of Mg²⁺ influx gradually increases between 30 and 60 min, and complete desensitization to (-)-isoproterenol occurs after about 60-70 min. In contrast, cyclic AMP accumulation after the addition of (-)-isoproterenol peaks within 3 min in wild-type S49 cells. The calculated rate of cyclic AMP synthesis in intact wild-type cells falls to zero after 3 min of incubation even though biologically active agonist is still present at a high concentration. This acute desensitization is not due to activation of phosphodiesterase since identical time courses are obtained either in wild-type cells with a phosphodiesterase inhibitor or in kinase^- S49 cells which have little or no detectable phosphodiesterase activity. These results indicate that -adrenergic stimulation of cyclic AMP accumulation and therefore adenylate cyclase desensitizes independently of -adrenergic inhibition of Mg²⁺ influx. Thus, not only is inhibition of Mg²⁺ transport by -adrenergic receptor occupancy not mediated by cyclic AMP, but this receptor-modulated transport event appears to be regulated independently of adenylate cyclase.

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ACKNOWLEDGMENTS We thank Paula L. Jacobs for excellent technical assistance and Drs. John J. Mieyal and Stephen A. Rudolph for their reading of the manuscript.