Extracellular calcium controls background current and neuronal excitability via an UNC79-UNC80-NALCN cation channel complex

Neuron. 2010 Nov 4;68(3):488-99. doi: 10.1016/j.neuron.2010.09.014.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Calcium / metabolism
  • Calcium / physiology
  • Calcium Channels / drug effects
  • Calcium Signaling / physiology*
  • Cell Line
  • Cloning, Molecular
  • Extracellular Space / physiology*
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Humans
  • Immunoprecipitation
  • Ion Channels / physiology*
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Nerve Tissue Proteins / physiology*
  • Neurons / drug effects
  • Neurons / physiology*
  • Patch-Clamp Techniques
  • Potassium Channels / drug effects
  • Receptors, G-Protein-Coupled / physiology
  • Sodium / metabolism
  • Substance P / pharmacology
  • Transfection


  • Calcium Channels
  • Ion Channels
  • Membrane Proteins
  • NALCN protein, mouse
  • Nerve Tissue Proteins
  • Potassium Channels
  • Receptors, G-Protein-Coupled
  • UNC-79 protein, mouse
  • UNC-80 protein, mouse
  • Substance P
  • Sodium
  • Calcium

Associated data

  • GENBANK/GQ334471