TY - JOUR
T1 - Peptide neurotransmitters activate a cation channel complex of NALCN and UNC-80
AU - Lu, Boxun
AU - Su, Yanhua
AU - Das, Sudipto
AU - Wang, Haikun
AU - Wang, Yan
AU - Liu, Jin
AU - Ren, Dejian
N1 - Funding Information:
Acknowledgements We thank D. Clapham, C. Deutsch, I. Medina, B. Novarro, M. Schmidt and H. Xu for critically reading earlier versions of the manuscript, J. Xia for help with experiments, H. Yu and L. Yue for cDNA constructs, and Sanofi-Aventis for the gift of SR48692. This work was supported, in part, by funding from American Heart Association, the NIH and the University of Pennsylvania Research Foundation.
PY - 2009/2/5
Y1 - 2009/2/5
N2 - 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.
AB - 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.
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U2 - 10.1038/nature07579
DO - 10.1038/nature07579
M3 - Article
C2 - 19092807
AN - SCOPUS:59649126876
SN - 0028-0836
VL - 457
SP - 741
EP - 744
JO - Nature
JF - Nature
IS - 7230
ER -