Intracellular Na + inhibits voltage‐dependent N‐type Ca 2+ channels by a G protein βγ subunit‐dependent mechanism

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 Gβγ 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 Gβγ‐dependent process. Na + ‐induced regulation of N‐VDCCs is Gβγ dependent, as suggested by the blocking of Na + effects by Gβγ scavengers and by excess Gβγ, and may be mediated by the Na + ‐induced dissociation of Gαβγ heterotrimers. N‐VDCCs may be novel effectors of Na + ion, regulated by the Na + concentration via Gβγ.