The sodium leak channel NALCN is regulated by neuronal SNARE complex proteins
NALCN (sodium leak channel, nonselective) is vital for regulating electrical activity in neurons and other excitable cells, and mutations in the channel or its auxiliary proteins lead to severe neurodevelopmental disorders. Here, we show that the neuronal SNARE (soluble <i>N</i>-ethylmaleimide-sensitive 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-containing complexes.
Authors
- Alexander Leitner (ORCID: https://orcid.org/0000-0003-4126-0725)
- Thorsten Trimbuch (ORCID: https://orcid.org/0000-0001-7512-8955)
- Prajakta Joshi (ORCID: https://orcid.org/0000-0003-4324-9976)
- Janne M. Colding
- Estelle Toulmé (ORCID: https://orcid.org/0000-0001-8734-3484)
- Roberta Florea (ORCID: https://orcid.org/0009-0002-2716-1560)
- Marc Kschonsak (ORCID: https://orcid.org/0000-0002-4392-1614)
- Alexander S. Hauser (ORCID: https://orcid.org/0000-0003-1098-6419)
- Inna Zilberleyb
- Stephan A. Pless (ORCID: https://orcid.org/0000-0001-6654-114X)
- Samuel Usher (ORCID: https://orcid.org/0000-0002-2487-6547)
- Christine C. Jao (ORCID: https://orcid.org/0009-0003-2597-8937)
- Bettina Brokowski
- Christian Rosenmund (ORCID: https://orcid.org/0000-0002-3905-2444)
- Stanislau Yatskevich (ORCID: https://orcid.org/0000-0003-2999-6561)
- Luuk Robin Hoegen Dijkhof (ORCID: https://orcid.org/0009-0007-6928-0513)
Institutions
- University of Copenhagen (DK)
- Genesys (United States) (US)
- ETH Zurich (CH)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- Science Advances
- Published
- 2025-03-14
- DOI
- https://doi.org/10.1126/sciadv.ads6004
- Citations
- 2
- Primary Topic
- Ion channel regulation and function
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Eidgenössische Technische Hochschule Zürich
- Lundbeckfonden
- H. Lundbeck A/S
- Genentech