Regulation of neuronal calcium channels by neurotransmitters, G proteins and kinase C

The regulation of voltage-dependent Ca channels by neurotransmitters and protein kinase C was examined under voltage-clamp in central and peripheral neurons freshly dissociated from Long Evans rats.; In pyramidal neurons from the CA3 region of the hippocampus, glutamate produced a rapid and reversible suppression of whole-cell Ca channel current. The pharmacology of the suppression by glutamate and various analogues was consistent with mediation by a metabotropic glutamate receptor. Selective metabotropic glutamate receptor agonists such as 1S,3R-ACPD produced suppression of Ca channel current without activation of glutamate-gated cation channels. The fraction of Ca channel current sensitive to 1S,3R-ACPD was largely, but not completely, blocked by {dollar}omega{dollar}-CgTx, but was insensitive to dihydropyridines. Experiments with guanine nucleotides suggested that metabotropic glutamate receptors suppress the activity of N-type Ca channels by a mechanism involving G proteins.; Baclofen, a selective agonist at GABA{dollar}sb{lcub}rm B{rcub}{dollar} receptors, also produced rapid and reversible suppression of whole-cell Ca channel current in CA3 pyramidal neurons. Baclofen suppressed a larger fraction of current when compared to glutamate and only about 50-60% of the current suppressed by baclofen was sensitive to {dollar}omega{dollar}-CgTx. A number of experiments suggested that GABA{dollar}sb{lcub}rm B{rcub}{dollar} receptors suppress the activity of Ca channels via a pathway similar to that used by metabotropic glutamate receptors.; Activation of protein kinase C dramatically reduced G protein-dependent suppression of Ca channel current by glutamate, GABA{dollar}sb{lcub}rm B{rcub},{dollar} adenosine, muscarinic, {dollar}alpha{dollar}-adrenergic and LHRH receptors in a variety of central and peripheral neurons. Inhibitors of protein kinase C were without effect on the inhibition of Ca channel current by these transmitters. Kinase C also disrupted G protein-mediated inhibition when the transmitter receptor was by-passed by directly activating G proteins with GTP-{dollar}gamma{dollar}-S.; Stimulation of protein kinase C also enhanced basal Ca channel current in a variety of neurons. In cerebral cortical and CA3 pyramidal neurons, about 70-80% of the kinase C enhanced current was {dollar}omega{dollar}-CgTx-sensitive; no evidence was found for enhancement of dihydropyridine-sensitive channels. The kinase C-induced enhancement of Ca channel current was voltage-dependent, and enhanced currents displayed altered kinetics. Inhibition of constitutive G protein-mediated inhibition with GDP-{dollar}beta{dollar}-S dramatically reduced the kinase C-induced enhancement of Ca channel current, suggesting that kinase C enhances Ca channel current, at least in part, by disrupting constitutive inhibition by G proteins. (Abstract shortened by UMI.)...