Extracellular Calcium Controls Background Current and Neuronal Excitability via an UNC79-UNC80-NALCN Cation Channel Complex

Summary In contrast to its extensively studied intracellular roles, the molecular mechanisms by which extracellular Ca 2+ regulates the basal excitability of neurons are unclear. One mechanism is believed to be through Ca 2+ 's interaction with the negative charges on the cell membrane (the charge screening effect). Here we show that, in cultured hippocampal neurons, lowering [Ca 2+ ] e activates a NALCN channel-dependent Na + -leak current (I L-Na ). The coupling between [Ca 2+ ] e and NALCN requires a Ca 2+ -sensing G protein-coupled receptor, an activation of G-proteins, an UNC80 protein that bridges NALCN to a large novel protein UNC79 in the same complex, and the last amino acid of NALCN's intracellular tail. In neurons from nalcn and unc79 knockout mice, I L-Na is insensitive to changes in [Ca 2+ ] e , and reducing [Ca 2+ ] e fails to elicit the excitatory effects seen in the wild-type. Therefore, extracellular Ca 2+ influences neuronal excitability through the UNC79-UNC80-NALCN complex in a G protein-dependent fashion.