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Regional differences in distribution and functional expression of small-conductance Ca2+-activated K+ channels in rat brain.

ABSTRACT: Small-conductance Ca2+-activated K+ (SK) channels are important for excitability control and afterhyperpolarizations in vertebrate neurons and have been implicated in regulation of the functional state of the forebrain. We have examined the distribution, functional expression, and subunit composition of SK channels in rat brain. Immunoprecipitation detected solely homotetrameric SK2 and SK3 channels in native tissue and their constitutive association with calmodulin. Immunohistochemistry revealed a restricted distribution of SK1 and SK2 protein with highest densities in subregions of the hippocampus and neocortex. In contrast, SK3 protein was distributed more diffusely in these brain regions and predominantly expressed in phylogenetically older brain regions. Whole-cell recording showed a sharp segregation of apamin-sensitive SK current within the hippocampal formation, in agreement with the SK2 distribution, suggesting that SK2 homotetramers underlie the apamin-sensitive medium afterhyperpolarizations in rat hippocampus.

SUBMITTER: Sailer CA

PROVIDER: S-EPMC6757844 | biostudies-literature | 2002 Nov

REPOSITORIES: biostudies-literature

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Regional differences in distribution and functional expression of small-conductance Ca2+-activated K+ channels in rat brain.

Sailer Claudia A CA Hu Hua H Kaufmann Walter A WA Trieb Maria M Schwarzer Christoph C Storm Johan F JF Knaus Hans-Günther HG

The Journal of neuroscience : the official journal of the Society for Neuroscience 20021101 22

Small-conductance Ca2+-activated K+ (SK) channels are important for excitability control and afterhyperpolarizations in vertebrate neurons and have been implicated in regulation of the functional state of the forebrain. We have examined the distribution, functional expression, and subunit composition of SK channels in rat brain. Immunoprecipitation detected solely homotetrameric SK2 and SK3 channels in native tissue and their constitutive association with calmodulin. Immunohistochemistry reveale ...[more]

PMID: 12427825

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Project description:Apamin-sensitive small-conductance Ca2+-activated K+ (SK) current ( IKAS) is encoded by Ca2+-activated K+ channel subfamily N ( KCNN) genes. IKAS importantly contributes to cardiac repolarization in conditions associated with reduced repolarization reserve. To test the hypothesis that IKAS inhibition contributes to drug-induced long QT syndrome (diLQTS), we screened for KCNN variants among patients with diLQTS, determined the properties of heterologously expressed wild-type (WT) and variant KCNN channels, and determined if the 5-HT3 receptor antagonist ondansetron blocks IKAS. We searched 2,306,335 records in the Indiana Network for Patient Care and found 11 patients with diLQTS who had DNA available in the Indiana Biobank. DNA sequencing discovered a heterozygous KCNN2 variant (p.F503L) in a 52-yr-old woman presenting with corrected QT interval prolongation at baseline (473 ms) and further corrected QT interval lengthening (601 ms) after oral administration of ondansetron. That patient was also heterozygous for the p.S38G and p.P2835S variants of the QT-controlling genes KCNE1 and ankyrin 2, respectively. Patch-clamp experiments revealed that the p.F503L KCNN2 variant heterologously expressed in human embryonic kidney (HEK)-293 cells augmented Ca2+ sensitivity, increasing IKAS density. The fraction of total F503L-KCNN2 protein retained in the membrane was higher than that of WT KCNN2 protein. Ondansetron at nanomolar concentrations inhibited WT and p.F503L SK2 channels expressed in HEK-293 cells as well as native SK channels in ventricular cardiomyocytes. Ondansetron-induced IKAS inhibition was also demonstrated in Langendorff-perfused murine hearts. In conclusion, the heterozygous p.F503L KCNN2 variant increases Ca2+ sensitivity and IKAS density in transfected HEK-293 cells. Ondansetron at therapeutic (i.e., nanomolar) concentrations is a potent IKAS blocker. NEW & NOTEWORTHY We showed that ondansetron, a 5-HT3 receptor antagonist, blocks small-conductance Ca2+-activated K+ (SK) current. Ondansetron may be useful in controlling arrhythmias in which increased SK current is a likely contributor. However, its SK-blocking effects may also facilitate the development of drug-induced long QT syndrome.

Dataset Information

Regional differences in distribution and functional expression of small-conductance Ca2+-activated K+ channels in rat brain.

Publications

Regional differences in distribution and functional expression of small-conductance Ca2+-activated K+ channels in rat brain.

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