Editors' ChoiceNeuroscience

More Substance to Excitation

Science Signaling  10 Feb 2009:
Vol. 2, Issue 57, pp. ec46
DOI: 10.1126/scisignal.257ec46

Substance P (SP) is a neuropeptide that causes slow excitation of neurons through SP-activated cation channel currents (ISP). The mechanisms involved in this slow excitation (including the identity of the channel) are unclear. Lu et al. investigated a role for NALCN, a neuronal cation channel, in mediating the effects of SP. Patch-clamp recordings showed that hippocampal pyramidal neurons from wild-type (WT), but not Nalcn–/–, mice responded to SP with an inward Na+ current that was blocked by an antagonist to TACR1, a G protein–coupled receptor for SP. Responses in Nalcn–/– neurons were rescued by transfection with a plasmid encoding Nalcn. Application of GTP or GDP analogs to lock G proteins into either “on” or “off” conformations, respectively, had no effect on ISP, suggesting that, although TACR1 was required for ISP, conventional G protein signaling was not. The Src family tyrosine kinase (SFK) inhibitor PP1 blocked ISP in neurons, whereas an SFK activator triggered an inward current (ISrc), which when it had plateaued rendered the neurons unresponsive to SP. ISrc did not occur in neurons from Nalcn–/– mice. Action potentials in ventral tegmental area dopaminergic neurons from WT, but not Nalcn–/–, animals were increased by SP, demonstrating a role for NALCN in SP-mediated modulation of neuronal excitability. No substantial ISP was detected in HEK 293T cells expressing TACR1 and NALCN; however, coexpression of a previously uncharacterized protein, UNC-80, whose gene interacts with Nalcn in other species, rendered the cells responsive to SP, which could be blocked by PP1. Taken together, these data suggest NALCN as the cation channel activated by SP in a G protein–independent, Src-dependent manner that involves UNC-80.

B. Lu, Y. Su, S. Das, H. Wang, Y. Wang, J. Liu, D. Ren, Peptide neurotransmitters activate a cation channel complex of NALCN and UNC-80. Nature 457, 741–744 (2009). [PubMed]