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Here, we show that the neuronal SNARE (soluble\n                    <jats:italic>N<\/jats:italic>\n                    -ethylmaleimide\u2013sensitive factor attachment protein receptors) complex proteins syntaxin and SNAP25 (synaptosome-associated protein 25), which enable synaptic transmission in the nervous system, inhibit the activity of the NALCN channel complex in both heterologous systems and primary neurons. The existence of this interaction suggests that the neurotransmitter release machinery can regulate electrical signaling directly and therefore modulate the threshold for its own activity. We further find that reduction of NALCN currents is sufficient to promote cell survival in syntaxin-depleted cells. This suggests that disinhibited NALCN may cause the puzzling phenomenon of rapid neuronal cell death in the absence of syntaxin. This interaction could offer opportunities for future drug development against genetic diseases linked to both NALCN- and SNARE protein\u2013containing complexes.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.ads6004","type":"journal-article","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T13:58:26Z","timestamp":1741960706000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":3,"title":["The sodium leak channel NALCN is regulated by neuronal SNARE complex proteins"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2487-6547","authenticated-orcid":true,"given":"Samuel","family":"Usher","sequence":"first","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen 2100, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8734-3484","authenticated-orcid":true,"given":"Estelle","family":"Toulm\u00e9","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Neurophysiologie, Charit\u00e9-Universit\u00e4tsmedizin, 10117 Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2716-1560","authenticated-orcid":true,"given":"Roberta","family":"Florea","sequence":"additional","affiliation":[{"name":"Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Otto-Stern-Weg 3, Z\u00fcrich 8093, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2999-6561","authenticated-orcid":true,"given":"Stanislau","family":"Yatskevich","sequence":"additional","affiliation":[{"name":"Department of Structural Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2597-8937","authenticated-orcid":true,"given":"Christine C.","family":"Jao","sequence":"additional","affiliation":[{"name":"Department of Structural Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6928-0513","authenticated-orcid":true,"given":"Luuk R. 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