Extracellular calcium controls background current and neuronal excitability via an UNC79-UNC80-NALCN cation channel complex.
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.
Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Boxun
B
Lu
Qi
Q
Zhang
Haikun
H
Wang
Yan
Y
Wang
Manabu
M
Nakayama
Dejian
D
Ren
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D015220:Calcium Channels / Q000187:drug effects; D020013:Calcium Signaling / Q000502:physiology*; D002460:Cell Line; D003001:Cloning, Molecular; D005110:Extracellular Space / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007473:Ion Channels / Q000502:physiology*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D012964:Sodium / Q000378:metabolism; D013373:Substance P / Q000494:pharmacology; D014162:Transfection
D015220:Calcium Channels; D007473:Ion Channels; D008565:Membrane Proteins; C519922:NALCN protein, mouse; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D043562:Receptors, G-Protein-Coupled; C553878:UNC-79 protein, mouse; C539144:UNC-80 protein, mouse; D013373:Substance P; D012964:Sodium; D002118:Calcium