Unplugging lateral fenestrations of NALCN reveals a hidden drug binding site within the pore region.

ABSTRACT: The sodium (Na⁺) leak channel (NALCN) is a member of the four-domain voltage-gated cation channel family that includes the prototypical voltage-gated sodium and calcium channels (Na_Vs and Ca_Vs, respectively). Unlike Na_Vs and Ca_Vs, which have four lateral fenestrations that serve as routes for lipophilic compounds to enter the central cavity to modulate channel function, NALCN has bulky residues (W311, L588, M1145, and Y1436) that block these openings. Structural data suggest that occluded fenestrations underlie the pharmacological resistance of NALCN, but functional evidence is lacking. To test this hypothesis, we unplugged the fenestrations of NALCN by substituting the four aforementioned residues with alanine (AAAA) and compared the

SUBMITTER: Schott K 

PROVIDER: S-EPMC11145269 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature