Loss-of-function K_Ca2.2 mutations abolish channel activity.

ABSTRACT: Small-conductance Ca²⁺-activated potassium channels subtype 2 (K_Ca2.2, also called SK2) are operated exclusively by a Ca²⁺-calmodulin gating mechanism. Heterozygous genetic mutations of K_Ca2.2 channels have been associated with autosomal dominant neurodevelopmental disorders including cerebellar ataxia and tremor in humans and rodents. Taking advantage of these pathogenic mutations, we performed structure-function studies of the rat K_Ca2.2 channel. No measurable current was detected from HEK293 cells heterologously expressing these pathogenic K_Ca2.2 mutants. When coexpressed with the K_Ca2.2_WT channel, mutations of the pore-lining amino acid residues (I360M, Y362C, G363S, and I389V) and two proline substitutions (L174P and L433P) dominant negatively suppressed and completely abolished the activity of the coexpressed K_Ca2.2_WT channel. Coexpression of the K_Ca2.2_I289N and the K_Ca2.2_WT channels reduced the apparent Ca²⁺ sensitivity compared with the K_Ca2.2_WT channel, which was rescued by a K_Ca2.2 positive modulator.

SUBMITTER: Nam YW 

PROVIDER: S-EPMC10069973 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature