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

SummaryIn contrast to its extensively studied intracellular roles, the molecular mechanisms by which extracellular Ca2+ regulates the basal excitability of neurons are unclear. One mechanism is believed to be through Ca2+'s interaction with the negative charges on the cell membrane (the charge screening effect). Here we show that, in cultured hippocampal neurons, lowering [Ca2+]e activates a NALCN channel-dependent Na+-leak current (IL-Na). The coupling between [Ca2+]e and NALCN requires a Ca2+-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, IL-Na is insensitive to changes in [Ca2+]e, and reducing [Ca2+]e fails to elicit the excitatory effects seen in the wild-type. Therefore, extracellular Ca2+ influences neuronal excitability through the UNC79-UNC80-NALCN complex in a G protein-dependent fashion.

► Extracellular Ca2+ controls the sizes of NALCN-dependent Na+-leak in hippocampal neurons ► Extracellular Ca2+ controls NALCN through GPCR, UNC79, and UNC80 ► UNC79 associates with NALCN via its association with UNC80 ► Hippocampal neurons from unc79 and nalcn knockout mice are not excited by lowering [Ca2+]e