Peptide neurotransmitters activate a cation channel complex of NALCN and UNC-80

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Abstract
Substance P is a neuropeptide that evokes slow excitation following activation of its cognate G-protein-coupled receptor. Lu et al. investigate the downstream pathway of substance P and show that it depends on Src family kinases rather than G-protein signalling. They also identify the target ion channel as the NALCN cation channel, which acts in complex with a cytosolic protein of unknown function, UNC-80. Substance P is a neuropeptide that evokes slow excitation after activation of its cognate G-protein-coupled receptor. This study investigates the downstream pathway and shows that it depends on Src family kinases, rather than G-protein signalling. 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.