Identification and characterization of a novel, shorter isoform of the small conductance Ca2+ -activated K+ channel SK2.
Throughout the CNS, small conductance Ca(2+)-activated potassium (SK) channels modulate firing frequency and neuronal excitability. We have identified a novel, shorter isoform of standard SK2 (SK2-std) in mouse brain which we named SK2-sh. SK2-sh is alternatively spliced at exon 3 and therefore lacks 140 amino acids, which include transmembrane domains S3, S4 and S5, compared with SK2-std. Western blot analysis of mouse hippocampal tissue revealed a 47 kDa protein product as predicted for SK2-sh along with a 64 kDa band representing the standard SK2 isoform. Electrophysiological recordings from transiently expressed SK2-sh revealed no functional channel activity or interaction with SK2-std. With the help of real-time PCR, we found significantly higher expression levels of SK2-sh mRNA in cortical tissue from AD cases when compared with age-matched controls. A similar increase in SK2-sh expression was induced in cortical neurons from mice by cytokine exposure. Substantial clinical evidence suggests that excess cytokines are centrally involved in the pathogenesis of Alzheimer's disease. Thus, SK2-sh as a downstream target of cytokines, provide a promising target for additional investigation regarding potential therapeutic intervention.
Murthy
Saravana R K
SR
Max Planck Institute for Experimental Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii 96813, USA.
Teodorescu
Georgeta
G
Nijholt
Ingrid M
IM
Dolga
Amalia M
AM
Grissmer
Stephan
S
Spiess
Joachim
J
Blank
Thomas
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D008970:Molecular Weight; D020033:Protein Isoforms / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*
D016207:Cytokines; C496898:Kcnn2 protein, mouse; D020033:Protein Isoforms; D012333:RNA, Messenger; D051640:Small-Conductance Calcium-Activated Potassium Channels