Activation of protein kinase C (PKC) reduced G protein-dependent inhibition of Ca2+ channels by glutamate, GA-BAB, adenosine, muscarinic, alpha-adrenergic, and LHRH receptors in a variety of central and peripheral neurons. PKC stimulation also relieved the inhibitory effect of internal GTP gamma S and reduced tonic G protein-mediated inhibition observed with internal GTP in the absence of transmitter receptor agonist. Basal Ca2+ channel currents were enhanced by PKC stimulation in most neurons studied. The PKC-induced enhancement of basal current was voltage dependent, and enhanced currents displayed altered kinetics. Inhibition of G proteins with GDP beta S attenuated the PKC-induced enhancement of basal Ca2+ channel current. These results show that PKC regulates the inhibitory effects of G proteins, possibly by disrupting the coupling of G proteins to Ca2+ channels. The PKC-induced enhancement of Ca2+ channel current results, at least in part, from the removal of tonic G protein-mediated inhibition.