BETA-ADRENERGIC-RECEPTOR DESENSITIZATION IN RAT ADIPOCYTE MEMBRANES

The ability of .beta.-adrenergic agonists to inactivate the .beta.-adrenergic receptors of rat white adipocytes was investigated using (-)-[3H]dihydroalprenolol as the .beta.-adrenergic ligand. When adipocyte membranes are successively exposed to (-)-isoproterenol at 25 or 4.degree. C, repeatedly washed and then incubated with [3H]dihydroalprenolol, 40-60% of the .beta.-receptors are lost. This loss (receptor desensitization) is rapid (half-life = 5-10 min), concentration-dependent and associated with a fall in the maximal receptor number with no significant change in the affinity of the remaining receptors for dihydroalprenolol and isoproterenol. Decreased binding is accompanied by decreased ability of isoproterenol to stimulate adenylate cyclase. Fat cell .beta.-receptor desensitization is stereospecific and characteristic of a .beta.1-receptor mediated process; the order of potency of agonists in inducing desensization is (-)-isoproterenol > (-)-norepinephrine > (-)-epinephrine > (+)-isoproterenol. Filipin and 5''-guanylylimidodiphosphate, a nucleotide which reduces the receptor affinity for the agonists, prevent and reverse the desensitization process, suggesting that the process is related to a poorly and slowly reversible high affinity binding of the agonist. The possible role of .beta.-receptor desensitization in the regulation of catecholamine-mediated process in adipocytes and in the catecholamine resistance of fat cells exposed to catecholamines is discussed.