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

Abstract

The modulation of Ca²⁺ channel activity by protein kinases contributes to the dynamic regulation of neuronal physiology. Using the transient expression of a family of neuronal Ca²⁺ channels, we have identified several factors that contribute to the PKC-dependent modulation of Ca²⁺ channels. First, the nature of the Ca²⁺ channel α₁ subunit protein is critical. Both α_1Bα_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 Ca²⁺ 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 Ca²⁺ channels by PKC and implicate α₁ and β subunit interactions in regulating channel activity via second messenger pathways.