Peptide neurotransmitters activate a cation channel complex of NALCN and UNC-80.
Several neurotransmitters act through G-protein-coupled receptors to evoke a 'slow' excitation of neurons. These include peptides, such as substance P and neurotensin, as well as acetylcholine and noradrenaline. Unlike the fast (approximately millisecond) ionotropic actions of small-molecule neurotransmitters, the slow excitation is not well understood at the molecular level, but can be mainly attributed to suppressing K(+) currents and/or activating a non-selective cation channel. The molecular identity of this cation channel has yet to be determined; similarly, how the channel is activated and its relative contribution to neuronal excitability induced by the neuropeptides are unknown. Here we show that, in the mouse hippocampal and ventral tegmental area neurons, substance P and neurotensin activate a channel complex containing NALCN and a large previously unknown protein UNC-80. The activation by substance P through TACR1 (a G-protein-coupled receptor for substance P) occurs by means of a unique mechanism: it does not require G-protein activation but is dependent on Src family kinases. These findings identify NALCN as the cation channel activated by substance P receptor, and suggest that UNC-80 and Src family kinases, rather than a G protein, are involved in the coupling from receptor to channel.
Lu
Boxun
B
Department of Biology, University of Pennsylvania, 415 S. University Avenue, Philadelphia, Pennsylvania 19104, USA.
Su
Yanhua
Y
Das
Sudipto
S
Wang
Haikun
H
Wang
Yan
Y
Liu
Jin
J
Ren
Dejian
D
D000818:Animals; D002460:Cell Line; D004553:Electric Conductivity; D006160:Guanosine Triphosphate / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007473:Ion Channels / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009496:Neurotensin / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013373:Substance P / Q000494:pharmacology; D014162:Transfection; D017557:Ventral Tegmental Area / Q000166:cytology; D019061:src-Family Kinases / Q000378:metabolism
D007473:Ion Channels; D008565:Membrane Proteins; C519922:NALCN protein, mouse; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D018040:Receptors, Neurokinin-1; C539144:UNC-80 protein, mouse; D013373:Substance P; D009496:Neurotensin; D006160:Guanosine Triphosphate; D019061:src-Family Kinases; D020962:Heterotrimeric GTP-Binding Proteins