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C100221200v1
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Papers In Press, published online ahead of print June 6, 2001
J. Biol. Chem, 10.1074/jbc.C100221200
Submitted on May 1, 2001
Revised on June 6, 2001
Accepted on June 6, 2001

Nuclear localization and dominant-negative suppression by a mutant SKCa3 N-terminal channel fragment identified in a patient with schizophrenia

Mark J. Miller, Heiko Rauer, Hiroaki Tomita, Heike Rauer, J. Jay Gargus, George A. Gutman, Michael D. Cahalan, and K. George Chandy

Department of Physiology and Biophysics, University of California Irvine, Irvine, CA 92697

Corresponding Author: gchandy{at}uci.edu

The small-conductance calcium-activated K+ channel gene SKCa3 / KCNN3 maps to 1q21, a region strongly linked to schizophrenia. Recently, a 4 bp deletion in SKCa3 was reported in a patient with schizophrenia. This frame-shift mutation would truncate the protein at the end of the N-terminal cytoplasmic region (SKCa3). We generated a GFP-SKCa3 N-terminal construct (SKCa3-1/285) that is identical to SKCa3 except for the last two residues. Using confocal microscopy we demonstrate that SKCa3-1/285 localizes rapidly and exclusively to the nucleus of mammalian cells like several other pathogenic polyglutamine containing proteins. This nuclear targeting is mediated in part by two polybasic sequences present at the C-terminal end of SKCa3-1/285. In contrast, full-length SKCa3, SKCa2 and IKCa1 polypeptides are all excluded from the nucleus and express as functional channels. When over-expressed in human Jurkat T cells, SKCa3-1/285 can suppress endogenous SKCa2 currents, but not voltage-gated K+ currents. This dominant negative suppression 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 ability to dominantly suppress endogenous SKCa currents may affect patterns of neuronal firing. Together, these two effects may play a part in the pathogenesis of schizophrenia and other neuropsychiatric disorders.


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