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Heterozygous genetic mutations of K<jats:sub>Ca<\/jats:sub>2.2 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<jats:sub>Ca<\/jats:sub>2.2 channel. No measurable current was detected from HEK293 cells heterologously expressing these pathogenic K<jats:sub>Ca<\/jats:sub>2.2 mutants. When coexpressed with the K<jats:sub>Ca<\/jats:sub>2.2_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<jats:sub>Ca<\/jats:sub>2.2_WT channel. Coexpression of the K<jats:sub>Ca<\/jats:sub>2.2_I289N and the K<jats:sub>Ca<\/jats:sub>2.2_WT channels reduced the apparent Ca<jats:sup>2+<\/jats:sup> sensitivity compared with the K<jats:sub>Ca<\/jats:sub>2.2_WT channel, which was rescued by a K<jats:sub>Ca<\/jats:sub>2.2 positive modulator. <\/jats:p>","DOI":"10.1152\/ajpcell.00584.2022","type":"journal-article","created":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T01:13:47Z","timestamp":1675127627000},"page":"C658-C664","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Loss-of-function K<sub>Ca<\/sub>2.2 mutations abolish channel activity"],"prefix":"10.1152","volume":"324","author":[{"given":"Young-Woo","family":"Nam","sequence":"first","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, California, United 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