Biology of Reproduction, Vol 22, 493-499, Copyright © 1980 by Society for the Study of Reproduction

Agonist-Dependent Desensitization of Myometrial -Adrenergic Catecholamine-Sensitive Adenylate Cyclase

¹ The Molecular Endocrinology Laboratory and The UCLA-San Fernando Valley Program, Veterans Administration Medical Center, Sepulveda, California 91343

Pretreatment of rats with the specific -adrenergic catecholamine agonist isoproterenol resulted in loss of adenylate cyclase sensitivity to the hormone in a subsequently prepared uterine smooth muscle particulate fraction. This agonist-mediated enzyme desensitization was accompanied by a rapid reduction in the smooth muscle cell concentration of -adrenergic catecholamine receptors determined by specific binding of the radioactive antagonist (—)-(³H)-dihydroalprenolol. Decrease in receptor number was not accompanied by a change in high affinity binding of the radioligand (Kd<5 nM) as determined by Scatchard analysis. Similar reductions in receptor concentration could be achieved by incubating muscle strips with isoproterenol in vitro at agonist doses <1.0 µM. Receptor down-regulation was blocked by the potent -adrenergic catecholamine antagonist (—)-alprenolol and reversed when the receptor-bearing microsomal fraction was exposed to guanylyl nucleotide. These results are more consistent with an agonist-induced change in receptor properties than with irreversible loss. Agonist-dependent down-regulation of the -adrenergic receptor accounts for adenylate cyclase desensitization in the myometrium and implies that these hormones have important selfregulating roles in the control of smooth muscle cell sensitivity and uterine motility.

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