Document Type
Article
Publication Date
1-30-2023
Abstract
Small-conductance Ca2+-activated potassium channels subtype 2 (KCa2.2, also called SK2) are operated exclusively by a Ca2+-calmodulin gating mechanism. Heterozygous genetic mutations of KCa2.2 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 KCa2.2 channel. No measurable current was detected from HEK293 cells heterologously expressing these pathogenic KCa2.2 mutants. When co-expressed with the KCa2.2_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 co-expressed KCa2.2_WT channel. Co-expression of the KCa2.2_I289N and the KCa2.2_WT channels reduced the apparent Ca2+ sensitivity compared with the KCa2.2_WT channel, which was rescued by a KCa2.2 positive modulator.
Recommended Citation
Nam Y-W, Rahman MA, Yang G, Orfali R, Cui M, Zhang M. Loss-of-function KCa2.2 mutations abolish channel activity. Am J Physiol Cell Physiol. 2023. https://doi.org/10.1152/ajpcell.00584.2022
Copyright
American Journal of Physiology-Cell Physiology
Included in
Animal Experimentation and Research Commons, Medical Neurobiology Commons, Medicinal and Pharmaceutical Chemistry Commons, Neurosciences Commons
Comments
This is a pre-copy-editing, author-produced PDF of an article accepted for publication in American Journal of Physiology-Cell Physiology in 2023 following peer review. This article may not exactly replicate the final published version. The definitive publisher-authenticated version is available online at https://doi.org/10.1152/ajpcell.00584.2022.