The neuronal channel NALCN contributes resting sodium permeability and is required for normal respiratory rhythm.
Sodium plays a key role in determining the basal excitability of the nervous systems through the resting "leak" Na(+) permeabilities, but the molecular identities of the TTX- and Cs(+)-resistant Na(+) leak conductance are totally unknown. Here we show that this conductance is formed by the protein NALCN, a substantially uncharacterized member of the sodium/calcium channel family. Unlike any of the other 20 family members, NALCN forms a voltage-independent, nonselective cation channel. NALCN mutant mice have a severely disrupted respiratory rhythm and die within 24 hours of birth. Brain stem-spinal cord recordings reveal reduced neuronal firing. The TTX- and Cs(+)-resistant background Na(+) leak current is absent in the mutant hippocampal neurons. The resting membrane potentials of the mutant neurons are relatively insensitive to changes in extracellular Na(+) concentration. Thus, NALCN, a nonselective cation channel, forms the background Na(+) leak conductance and controls neuronal excitability.
Lu
Boxun
B
Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Su
Yanhua
Y
Das
Sudipto
S
Liu
Jin
J
Xia
Jingsheng
J
Ren
Dejian
D
D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002490:Central Nervous System / Q000166:cytology; D002586:Cesium / Q000494:pharmacology; D018076:DNA, Complementary; D004622:Embryo, Mammalian / Q000378:metabolism; D004625:Embryo, Nonmammalian; D005804:Genes, Lethal; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007473:Ion Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D051381:Rats; D012119:Respiration; D016415:Sequence Alignment; D012964:Sodium / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D014162:Transfection; D014981:Xenopus
D018076:DNA, Complementary; D007473:Ion Channels; D008565:Membrane Proteins; C519922:NALCN protein, mouse; D009419:Nerve Tissue Proteins; D002586:Cesium; D013779:Tetrodotoxin; D012964:Sodium; D011188:Potassium; D002118:Calcium