Nuclear localization and dominant-negative suppression by a mutant SKCa3N-terminal channel fragment identified in a patient with schizophrenia

The small conductance calcium-activated K+ channel gene SKCa3/KCNN3 maps to 1q2l, a region strongly linked to schizophrenia. Recently, a 4-base pair d eletion in SKCa3 was reported in a patient with schizophrenia, which trunca tes the protein at the end of the N-terminal cytoplasmic region (SKCa3 Delt a). We generated a green fluorescent protein-SKCa3 N-terminal construct (SK Ca3-1/285) that is identical to SKCa3 Delta except for the last two residue s. Using confocal microscopy we demonstrate that SKCa3-1/285 localizes rapi dly and exclusively to the nucleus of mammalian cells like several other pa thogenic polyglutamine-containing proteins. This nuclear targeting is media ted in part by two polybasic sequences present at the C-terminal end of SKC a3-1/285. In contrast, full-length SKCa3, SKCa2, and IKCal polypeptides are all excluded from the nucleus and express as functional channels. When ove rexpressed in human Jurkat T cells, SKCa3-1/285 can suppress endogenous SKC a2 currents but not voltage-gated K+ currents. This dominant-negative suppr ession is most likely mediated through the co-assembly of SKCa3-1/285 with native subunits and the formation of non-functional tetramers. The nuclear localization of SKCa3-1/285 may alter neuronal architecture, and its abilit y to dominantly suppress endogenous small conductance K-Ca currents may aff ect patterns of neuronal firing. Together, these two effects may play a par t in the pathogenesis of schizophrenia and other neuropsychiatric disorders .