Molecular Pharmacology, Vol 15, 462-471, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

Desensitization of Histamine H₁ Receptor-Mediated Cyclic GMP Formation in Mouse Neuroblastoma Cells

¹ Departments of Psychiatry and Pharmacology, Mayo Foundation, Rochester, Minnesota 55901

Histamine H₁ receptor-mediated cyclic GMP formation by intact mouse neuroblastoma cells (clone N1E-115) was attenuated by prolonged exposure to histamine. This desensitization was dependent upon the concentration of histamine and at 10 µM the half-time was 9 min, whereas the half-time for resensitization in the absence of histamine was 13 min. The order of potency for agonist-induced desensitization correlated with the order of potency for stimulating the H₁ receptor (histamine > 2-methylhistamine; 4-methylhistamine, no effect). Pyrilamine (50 nM) was more potent than metiamide (15 µM) in blocking desensitization by histamine. The ED₅₀ for activation and for desensitization by histamine of the receptor-mediated response was approximately equal to its K_A for the H₁ receptor. Omission of Ca⁺⁺ in the medium prevented cyclic GMP formation, but did not affect desensitization, suggesting that cyclic GMP formation was not required for the development of the desensitized state. Desensitization was temperature-dependent and marked inhibition of protein synthesis did not affect desensitization or its reversal. Finally, the ED₅₀'s for histamine-stimulated cyclic GMP formation in control and in partially desensitized cells were similar while the maximum response was reduced.

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ACKNOWLEDGMENTS The authors thank Drs. J. R. Blinks and F. G. Prendergast for helpful discussions.