Alterations in histamine receptors of guinea-pig ileal smooth muscle produced during agonist-induced desensitization.

1. The effects of prolonged treatment with histamine (10(-4) M, 30 min) on desensitization at histamine H1-receptors of guinea-pig ileal longitudinal muscle were investigated. 2. This treatment did not change either the maximum amount or dissociation constant (Kd) of [3H]-mepyramine binding to membranes of guinea-pig ileal muscle. 3. In contrast, this treatment shifted the histamine inhibition curves of [3H]-mepyramine binding to the right both in the presence and absence of 0.5 mM guanosine-5'-triphosphate (GTP). This rightward shift of the curves occurred rapidly in the first 10 min of exposure to histamine. 4. The histamine inhibition curves were analyzed with a two binding sites model. It was shown that the histamine-induced affinity change of the receptor for the agonist occurred with the high affinity binding component (which comprise about 80% of the total), whereas no significant change occurred with the low affinity component. The GTP-dependent decrease in the affinity of the receptor for the agonist also occurred with the high affinity component both in control and histamine-treated preparations. 5. These studies suggest that histamine-induced desensitization was caused by alteration in the affinity of the receptor for the agonist rather than reduction in the number of the receptors and that the interaction of the receptor with a guanine nucleotide regulatory protein was retained in the desensitized state.