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.