N-type voltage-dependent Ca(2+) channels (N-VDCCs) play important roles in neurotransmitter release and certain postsynaptic phenomena. These channels are modulated by a number of intracellular factors, notably by Gbetagamma subunits of G proteins, which inhibit N-VDCCs in a voltage-dependent (VD) manner. Here we show that an increase in intracellular Na(+) concentration inhibits N-VDCCs in hippocampal pyramidal neurones and in Xenopus oocytes. In acutely dissociated hippocampal neurones, Ba(2+) current via N-VDCCs was inhibited by Na(+) influx caused by the activation of NMDA receptor channels. In Xenopus oocytes expressing N-VDCCs, Ba(2+) 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 a Gbetagamma-dependent process. Na(+)-induced regulation of N-VDCCs is Gbetagamma dependent, as suggested by the blocking of Na(+) effects by Gbetagamma scavengers and by excess Gbetagamma, and may be mediated by the Na(+)-induced dissociation of Galphabetagamma heterotrimers. N-VDCCs may be novel effectors of Na(+)ion, regulated by the Na(+) concentration via Gbetagamma.