Homologous Desensitization of Muscarinic Cholinergic, Histaminergic, Adrenergic, and Serotonergic Receptors Coupled to Phospholipase C in Cerebellar Granule Cells

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Abstract
Cultured cerebellar granule cells express phospholipase C-coupled muscarinic cholinergic, histaminergic, α1-adrenergic, and serotonergic receptors. In an attempt to study desensitization of these neurotransmitter receptors, cells were prestimulated with saturating concentrations of carbachol, histamine, norepinephrine, or serotonin during the labeling of cells with myo-[3H]inositol and then rechallenged with various receptor agonists for their ability to elicit accumulation of [3H]inositol monophosphate in the presence of lithium. Prestimulation with each of these receptor agonists was found to cause a time-dependent desensitization to subsequent stimulation with the desensitizing agonist. Thus, prestimulation for 0.5, 4, and 18 h decreased carbachol response to 87 ± 4, 52 ± 2, and 40 ± 1% of the control, respectively; histamine response to 37 ± 2, 24 ± 2, and 18 ± 2%, respectively; norepinephrine response to 55 ± 5, 14 ± 1, and 10 ± 1%, respectively; and serotonin response to 36 ± 1, 18 ± 1, and 9 ± 2%, respectively. In all cases, the responses mediated by receptors which were not prestimulated remained virtually unchanged, thus indicating homologous desensitization. Dose-response studies indicate that the desensitization was associated with a major reduction in the maximal extent of agonist-induced responses. The basal accumulation was markedly enhanced following 0.5- and 4-h prestimulation, but returned to near normal after 18-h pretreatment. Biologically active phorbol ester, 4β-phorbol 12-myristate 13-acetate, rapidly attenuated basal phospholipase C activity, as well as the responses mediated by carbachol, histamine, norepinephrine, and serotonin, suggesting that activation and translocation of protein kinase C might play a role in the desensitization of phospholipase C-coupled receptors. Possible mechanisms of homologous desensitization of receptors in granule cells are discussed.

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