%0 Journal Article %A MICHAEL R. WESSELS %A DEBRA MULLIKIN %A ROBERT J. LEFKOWITZ %T Selective Alteration in High Affinity Agonist Binding: A Mechanism of Beta-Adrenergic Receptor Desensitization %D 1979 %J Molecular Pharmacology %P 10-20 %V 16 %N 1 %X Beta-adrenergic receptor desensitization of intact frog erythrocytes results in a greater percent fall in agonist ((±)[3H]hydroxybenzylisoproterenol) than in antagonist ((-)[3H]-dihydroalprenolol) binding. We now report the results of detailed studies on the alterations in agonist binding associated with beta-adrenergic receptor desensitization. Competition binding experiments revealed a lower overall affinity of agonist binding after desensitization. The affinity of antagonist ([3H]dihydroalprenolol) binding appeared unchanged after desensitization. Three reagents (N-ethylmaleimide, EDTA, and Gpp(NH)p) that decrease high affinity agonist binding were shown to have less effect on [3H]hydroxybenzylisoproterenol binding after desensitization. Two such agents (N-ethylmaleimide and dicyclohexyl carbodiimide) were also shown to block desensitization of intact cells. Guanine nucleotides failed to restore beta-adrenergic antagonist ([3H]dihydroalprenolol) binding sites after desensitization. Adenylate cyclase catalytic activity was not impaired by desensitization and remained normally responsive to guanine nucleotides. These findings are consistent with a model of beta-adrenergic receptor desensitization in which desensitized receptors arise from receptors in the high affinity state, with chronic occupancy by agonist. The process of desensitization thus appears to result in selective loss or inactivation of these high affinity agonist binding sites. %U https://molpharm.aspetjournals.org/content/molpharm/16/1/10.full.pdf