N-type voltage dependent Ca2+ channels (N-VDCC) play important roles in neurotransmitter release and certain postsynaptic phenomena. These channels are modulated by a number of intracellular factors, notably by G subunits of G proteins, which inhibit N-VDCCs in a voltage-dependent (VD) manner. Here we show that increase in intracellular Na+ concentration inhibits N-VDCC in hippocampal pyramidal neurons and in Xenopus oocytes. In acutely dissociated hippocampal neurons, Ba2+ current via N-VDCC was inhibited by Na+ influx caused by activation of NMDA receptor channels. In Xenopus oocytes expressing N-VDCC, Ba2+ currents were inhibited by Na+ influx and enhanced by depletion of Na+, after incubation in a Na+-free extracellular solution. The Na+-induced inhibition was accompanied by the development of VD facilitation, a hallmark of G-dependent process. Na+-induced regulation of N-VDCCs is G-dependent, as suggested by block of Na+ effects by G scavengers and by excess G, and may be mediated by Na+ -induced dissociation of G heterotrimers. N-VDCC may be a novel effector of Na+, regulated by the latter via G.