Muscarinic Regulation of Ca2+Currents in Rat Sensory Neurons: Channel and Receptor Types, Dose - response Relationships and Cross-talk Pathways

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Abstract
We studied, in rat sensory neurons, the modulation of high voltage‐activated Ca2+ currents (ICa mediated by the pertussis toxin‐sensitive activation of muscarinic receptors, which were found to be of subtypes M2, or M4. Muscarine reversibly blocked somatic Ca2+ spikes but strong predepolarizations only partially relieved the inhibited Ca2+ current. On the other hand, the putative coupling messenger could not rapidly diffuse towards channels whose activity was recorded from a macro‐patch. The perforated patch technique virtually prevented the response rundown present during whole‐cell experiments. Both ω‐conotoxin GVIA (ω‐CgTx)‐sensitive channels and ω‐CgTx‐ and dihydropyridine‐resistant channels are coupled to the muscarinic receptor, but not the L‐channel. When measured in the same neuron, dose ‐ response relationships for the first and subsequent agonist applications differed; maximal inhibition, the reciprocal of half‐maximal concentration and the Hill coefficient were always highest in the first trial. Muscarine and oxotremorine exhibited monotone dose ‐ response curves, but oxotremorine‐M showed non‐linear relationships which became monotonic when cells were intracellularly perfused with inhibitors of protein kinase A (PKA) and C (PKC), suggesting that either PKA or receptor‐induced PKC could phosphorylate and thus inactivate G‐proteins or other unknown proteins involved in inhibitory muscarinic actions on ICa. In summary, these data provide a preliminary pharmacological characterization of the muscarinic inhibition of the Ca2+ channels in sensory neurons, with implications about agonist specificity and the interplay between signalling pathways.