Determinants of PKC-dependent modulation of a family of neuronal calcium channels

Abstract The modulation of Ca 2+ channel activity by protein kinases contributes to the dynamic regulation of neuronal physiology. Using the transient expression of a family of neuronal Ca 2+ channels, we have identified several factors that contribute to the PKC-dependent modulation of Ca 2+ channels. First, the nature of the Ca 2+ channel α 1 subunit protein is critical. Both α 1B α 1E channels exhibit a 30%–40% increase in peak currents after exposure to phorbol esters, whereas neither α 1A nor α 1C channels are significantly affected. This up-regulation can be mimicked for α 1E channels by stimulation of a coexpressed metabotropic glutamate receptor (type 1α) through a PKC-dependent pathway. Second, PKC-stimulated up-regulation is dependent upon coexpression with a Ca 2+ channel β subunit. Third, substitution of the cytoplasmic domain I–II linker from α 1B confers PKC sensitivity to α 1A channels. The results provide direct evidence for the modulation of a subset of neuronal Ca 2+ channels by PKC and implicate α 1 and β subunit interactions in regulating channel activity via second messenger pathways.