The sodium leak channel NALCN is regulated by neuronal SNARE complex proteins

被引:0
|
作者
Usher, Samuel [1 ]
Toulme, Estelle [2 ]
Florea, Roberta [3 ]
Yatskevich, Stanislau [4 ]
Jao, Christine C. [4 ]
Dijkhof, Luuk R. H. [1 ]
Colding, Janne M. [1 ]
Joshi, Prajakta [5 ]
Zilberleyb, Inna [5 ]
Trimbuch, Thorsten [2 ]
Brokowski, Bettina [2 ]
Hauser, Alexander S. [1 ]
Leitner, Alexander [3 ]
Rosenmund, Christian [2 ]
Kschonsak, Marc [4 ]
Pless, Stephan A. [1 ]
机构
[1] Univ Copenhagen, Dept Drug Design & Pharmacol, DK-2100 Copenhagen, Denmark
[2] Charite, Inst Neurophysiol, D-10117 Berlin, Germany
[3] Swiss Fed Inst Technol, Inst Mol Syst Biol, Dept Biol, Otto Stern Weg 3, CH-8093 Zurich, Switzerland
[4] Genentech Inc, Dept Struct Biol, 1 DNA Way, South San Francisco, CA 94080 USA
[5] Genentech Inc, Dept Biomol Resources, 1 DNA Way, South San Francisco, CA 94080 USA
来源
SCIENCE ADVANCES | 2025年 / 11卷 / 11期
关键词
CFTR CHLORIDE CHANNELS; SYNTAXIN; 1A; N-TYPE; CONFORMATIONAL SWITCH; SURFACE EXPRESSION; FUNCTIONAL IMPACT; K+ CHANNEL; MODULATION; PEPTIDES; BINDING;
D O I
10.1126/sciadv.ads6004
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 N-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.
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页数:17
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