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bioRxiv · 10.1101/740456

The sodium leak channel complex is modulated by voltage and extracellular calcium

Chua, H. C.·Wulf, M.·Weidling, C.·Rasmussen, L. P.·Pless, S. A.
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Abstract

The sodium leak channel (NALCN) is essential for survival in mammals: NALCN mutations are life-threatening in humans and knockout is lethal in mice. However, the basic functional and pharmacological properties of NALCN have remained elusive. Here, we found that the robust function of NALCN in heterologous systems requires co-expression of UNC79, UNC80 and FAM155A. The resulting NALCN channel complex is constitutively active, conducts monovalent cations but is blocked by physiological concentrations of extracellular divalent cations. Our data support the notion that NALCN is directly responsible for the increased excitability observed in a variety of neurons in reduced extracellular Ca2+. Despite the smaller number of voltage-sensing residues in the putative voltage sensors of NALCN, the channel complex shows voltage-dependent modulation of the constitutive current, suggesting that voltage-sensing domains can give rise to a broader range of gating phenotypes than previously anticipated. Our work points towards formerly unknown contributions of NALCN to neuronal excitability and opens avenues for pharmacological targeting. HighlightsO_LIFunction of NALCN requires UNC79, UNC80 and FAM155A C_LIO_LIThe complex is permeable to monovalent cations, but is blocked by divalent cations C_LIO_LIThe complex displays a constitutively active, voltage-modulated current phenotype C_LIO_LIPositively charged side chains in S4 of NALCN VSD I and II confer voltage sensitivity C_LI

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Chua, H. C., Wulf, M., Weidling, C., Rasmussen, L. P., Pless, S. A.. 2019-08-20. The sodium leak channel complex is modulated by voltage and extracellular calcium. https://doi.org/10.1101/740456

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