RT Journal Article SR Electronic T1 The NALCN channel complex is voltage sensitive and directly modulated by extracellular calcium JF Science Advances JO Sci Adv FD American Association for the Advancement of Science SP eaaz3154 DO 10.1126/sciadv.aaz3154 VO 6 IS 17 A1 Chua, H. C. A1 Wulf, M. A1 Weidling, C. A1 Rasmussen, L. P. A1 Pless, S. A. YR 2020 UL http://advances.sciencemag.org/content/6/17/eaaz3154.abstract AB 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 robust function of NALCN in heterologous systems requires co-expression of UNC79, UNC80, and FAM155A. The resulting NALCN channel complex is constitutively active and 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 NALCN, the constitutive activity is modulated by voltage, suggesting that voltage-sensing domains can give rise to a broader range of gating phenotypes than previously anticipated. Our work points toward formerly unknown contributions of NALCN to neuronal excitability and opens avenues for pharmacological targeting.