Many human hereditary neurodegenerative diseases are caused by expanded CAG repeats, and anonymous CAG expansions have also been described in schizophrenia and bipolar disorder. We have isolated and sequenced a novel human cDNA encoding a neuronal, small conductance calcium-activated potassium channel (hSKCa3) that contains two arrays of CAG trinucleotide repeats. The second CAG repeat in hSKCa3 is highly polymorphic in control individuals, with alleles ranging in size from 12 to 28 repeats. The overall allele frequency distribution is significantly different in patients with schizophrenia compared to ethnically matched controls (Wilcoxon Rank Sum test, P = 0.024), with CAG repeats longer than the modal value being over-represented in patients (Fisher Exact test, P = 0.0035). A similar, non-significant, trend is seen for patients with bipolar disorder. These results provide evidence for a possible association between longer alleles in the hSKCa3 gene and both of these neuropsychiatric diseases, and emphasize the need for more extensive studies of this new gene. Small conductance calcium-activated K + channels play a critical role in determining the firing pattern of neurons. These polyglutamine repeats may modulate hSKCa3 channel function and neuronal excitability, and thereby increase disease risk when combined with other genetic and environmental effects.

Apamin-sensitive small conductance calcium-activated potassium channels (SKCa1-3) mediate the slow afterhyperpolarization in neurons, but the molecular identity of the channel has not been defined because of the lack of specific inhibitors. Here we describe the structure-based design of a selective inhibitor of SKCa2. Leiurotoxin I (Lei) and PO5, peptide toxins that share the RXCQ motif, potently blocked human SKCa2 and SKCa3 but not SKCa1, whereas maurotoxin, Pi1, Ts, and PO1 were ineffective. Lei blocked these channels more potently than PO5 because of the presence of

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Ion channels are a large family of >400 related proteins representing >1% of our genetic endowment; however, ion-channel diseases reflect a relatively new category of inborn error. They were first recognized in 1989, with the discovery of cystic fibrosis transmembrane conductance regulator, and rapidly advanced as positional and functional studies converged in the dissection of components of the action potential of excitable tissues. Although it remains true that diseases of excitable tissue still most clearly illustrate this family of disease, ion-channel disorders now cover the gamut of medical disciplines, causing significant pathology in virtually every organ system, producing a surprising range of often unanticipated symptoms, and providing valuable targets for pharmacological intervention. Many of the features shared among the monogenic ion-channel diseases provide a general framework for formulating a foundation for considering their intrinsically promising role in polygenic disease. Since an increasingly important approach to the identification of genes underlying polygenic disease is to identify "functional candidates" within a critical region and to test their disease association, it becomes increasingly important to appreciate how these ion-channel mechanisms can be implicated in pathophysiology.

The small conductance calcium-activated K ؉ channel gene SKCa3/KCNN3 maps to 1q21, a region strongly linked to schizophrenia. Recently, a 4-base pair deletion in SKCa3 was reported in a patient with schizophrenia, which truncates the protein at the end of the N-terminal cytoplasmic region (SKCa3⌬). We generated a green fluorescent protein-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 overexpressed 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 small conductance K Ca currents may affect patterns of neuronal firing. Together, these two effects may play a part in the pathogenesis of schizophrenia and other neuropsychiatric disorders.