Intracellular Na+ inhibits voltage-dependent N-type Ca2+ channels by a G protein βγ subunit-dependent mechanism

N-type voltage-dependent Ca2+ 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, Ba2+ current via N-VDCCs was inhibited by Na+ influx caused by the activation of NMDA receptor channels. In Xenopus oocytes expressing N-VDCCs, 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 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.