Several neurotransmitters act through G-protein-coupled receptors to evoke a ‘slow’ excitation of neurons1,2. 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 channel3,4,5,6,7,8,9. 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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The sequence of mUNC-80 is deposited in GenBank under accession number FJ210934.
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.
Author Contributions B.L. did recordings from neurons (Figs 1–3 and Supplementary Fig. 2) and all the HEK293T cells (Fig. 4 and Supplementary Figs 1 and 7–10). Y.S. contributed to neuronal recordings (Figs 1 and 2 and Supplementary Figs 3 and 4). S.D. contributed to work in Fig. 2. H.W., Y.W. and J.L. did the protein work (Fig. 4 and Supplementary Fig. 6). D.R. started the project, designed experiments and developed the cDNA constructs. B.L. and D.R. wrote the paper.
This file contains Supplementary Figures 1-10 with Legends