Association of Moderate Polyglutamine Tract Expansions in the Slow Calcium-Activated Potassium Channel Type 3 With Ataxia

Figueroa, Karla P.; Chan, Piu; Schöls, Lüdger; Tanner, Carline; Riess, O.; Perlman, Susan; Geschwind, Daniel H.; Pulst, Stefan M.

doi:10.1001/archneur.58.10.1649

Cited by 23 publications

(17 citation statements)

References 31 publications

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“…Excess SK3-1B, in turn, would be predicted to affect dopaminergic pathways in the brain in the manner implicated in current biological models of schizophrenia. 12,14 Further, SK3 has recently been implicated in anorexia nervosa 4 and ataxia, 5 and alterations in the SK3/SK3-1B balance may contribute to the pathogenesis of these diseases as well.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 Functional SK channels are formed from the homo-or heterotetramericassociation of products of three related genes, SK1-SK3 (also known as KCNN1-KCNN3 and SKCa1-SKCa3). 3 Several lines of evidence have implicated the SK3 channel in schizophrenia, and more recently in anorexia nervosa 4 and ataxia, 5 although the results are not conclusive. The SK3 gene is located on human chromosome 1q21 6 in a region containing a major susceptibility locus for familial schizophrenia [7][8][9] and familial hemiplegic migraine associated with permanent cerebellar ataxia.…”

Section: Introductionmentioning

confidence: 99%

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Novel truncated isoform of SK3 potassium channel is a potent dominant-negative regulator of SK currents: implications in schizophrenia

et al. 2003

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The small-conductance calcium-activated K þ channel SK3 (SKCa3/KCNN3) regulates electrical excitability and neurotransmitter release in monoaminergic neurons, and has been implicated in schizophrenia, ataxia and anorexia nervosa. We have identified a novel SK3 transcript, SK3-1B that utilizes an alternative first exon (exon 1B), but is otherwise identical to SK3. SK3-1B, mRNA is widely distributed in human tissues and is present at 20-60% of SK3 in the brain. The SK3-1B protein lacks the N-terminus and first transmembrane segment, and begins eight residues upstream of the second transmembrane segment. When expressed alone, SK3-1B did not produce functional channels, but selectively suppressed endogenous SK3 currents in the pheochromocytoma cell line, PC12, in a dominant-negative fashion. This dominant inhibitory effect extended to other members of the SK subfamily, but not to voltage-gated K þ channels, and appears to be due to intracellular trapping of endogenous SK channels. The effect of SK3-1B expression is very similar to that produced by expression of the rare SK3 truncation allele, SK3-D, found in a patient with schizophrenia. Regulation of SK3 and SK3-1B levels may provide a potent mechanism to titrate neuronal firing rates and neurotransmitter release in monoaminergic neurons, and alterations in the relative abundance of these proteins could contribute to abnormal neuronal excitability, and to the pathogenesis of schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel truncated isoform of SK3 potassium channel is a potent dominant-negative regulator of SK currents: implications in schizophrenia

et al. 2003

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“…Cerebellar ataxia, a disease characterized by incoordination, instability of posture, gait abnormalities, and intention tremor, has many molecular causes (1)(2)(3)(4)(5). Hereditary cerebellar ataxias are slowly progressive, and the genes responsible for 50-60% of hereditary ataxias have been identified, but the molecular basis for the others, as well as for sporadic ataxias, remains elusive (1)(2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

“…Hereditary cerebellar ataxias are slowly progressive, and the genes responsible for 50-60% of hereditary ataxias have been identified, but the molecular basis for the others, as well as for sporadic ataxias, remains elusive (1)(2)(3)(4)(5). Cerebellar cortical degeneration is a hallmark of this disease, and, irrespective of the nature of the cerebellar cortical defect, degeneration results in altered Purkinje neuron output (3).…”

Section: Introductionmentioning

confidence: 99%

Enhanced neuronal excitability in the absence of neurodegeneration induces cerebellar ataxia

Shakkottai¹,

Chou²,

Oddo³

et al. 2004

J. Clin. Invest.

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Cerebellar ataxia, a devastating neurological disease, may be initiated by hyperexcitability of deep cerebellar nuclei (DCN) secondary to loss of inhibitory input from Purkinje neurons that frequently degenerate in this disease. This mechanism predicts that intrinsic DCN hyperexcitability would cause ataxia in the absence of upstream Purkinje degeneration. We report the generation of a transgenic (Tg) model that supports this mechanism of disease initiation. Small-conductance calciumactivated potassium (SK) channels, regulators of firing frequency, were silenced in the CNS of Tg mice with the dominant-inhibitory construct SK3-1B-GFP. Transgene expression was restricted to the DCN within the cerebellum and was detectable beginning on postnatal day 10, concomitant with the onset of cerebellar ataxia. Neurodegeneration was not evident up to the sixth month of age. Recordings from Tg DCN neurons revealed loss of the apamin-sensitive after-hyperpolarization current (I AHP ) and increased spontaneous firing through SK channel suppression, indicative of DCN hyperexcitability. Spike duration and other electrogenic conductance were unaffected. Thus, a purely electrical alteration is sufficient to cause cerebellar ataxia, and SK openers such as the neuroprotective agent riluzole may reduce neuronal hyperexcitability and have therapeutic value. This dominant-inhibitory strategy may help define the in vivo role of SK channels in other neuronal pathways.

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“…Several lines of evidence have implicated SK3 in schizophrenia (9,(22)(23)(24)(25)(26)(27), but these results are controversial because other studies have failed to confirm this disease association (28 -35). SK3 has also been associated with anorexia nervosa (36), and dominant cerebellar ataxia (37), and has been reported to underlie the hyperexcitability associated with skeletal muscle denervation (2,38).…”

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confidence: 99%

SK3-1C, a Dominant-negative Suppressor of SKCa and IKCa Channels

Kolski-Andreaco

Tomita

Shakkottai

et al. 2004

Journal of Biological Chemistry

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Small conductance Ca 2؉ -activated K ؉ channels, products of the SK1-SK3 genes, regulate membrane excitability both within and outside the nervous system. We report the characterization of a SK3 variant (SK3-1C) that differs from SK3 by utilizing an alternative first exon (exon 1C) in place of exon 1A used by SK3, but is otherwise identical to SK3. Quantitative RT-PCR detected abundant expression of SK3-1C transcripts in human lymphoid tissues, skeletal muscle, trachea, and salivary gland but not the nervous system. SK3-1C did not produce functional channels when expressed alone in mammalian cells, but suppressed SK1, SK2, SK3, and IKCa1 channels, but not BK Ca or K V channels. Confocal microscopy revealed that SK3-1C sequestered SK3 protein intracellularly. Dominant-inhibitory activity of SK3-1C was not due to a nonspecific calmodulin sponge effect since overexpression of calmodulin did not reverse SK3-1C-mediated intracellular trapping of SK3 protein, and calmodulin-Ca 2؉ -dependent inactivation of Ca V channels was not affected by SK3-1C overexpression. Deletion analysis identified a dominant-inhibitory segment in the SK3-1C C terminus that resembles tetramerization-coiled-coiled domains reported to enhance tetramer stability and selectivity of multimerization of many K ؉ channels. SK3-1C may therefore suppress calmodulin-gated SK Ca /IK Ca channels by trapping these channel proteins intracellularly via subunit interactions mediated by the dominant-inhibitory segment and thereby reduce functional channel expression on the cell surface. Such family-wide dominant-negative suppression by SK3-1C provides a powerful mechanism to titrate membrane excitability and is a useful approach to define the functional in vivo role of these channels in diverse tissues by their targeted silencing.

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Association of Moderate Polyglutamine Tract Expansions in the Slow Calcium-Activated Potassium Channel Type 3 With Ataxia

Abstract: Longer stretches of polyglutamines in a human potassium channel are not causative for ataxia, but they are associated with the presence of ataxia. There is no association with the presence of Parkinson disease.

Cited by 23 publications

References 31 publications

Novel truncated isoform of SK3 potassium channel is a potent dominant-negative regulator of SK currents: implications in schizophrenia

Novel truncated isoform of SK3 potassium channel is a potent dominant-negative regulator of SK currents: implications in schizophrenia

Enhanced neuronal excitability in the absence of neurodegeneration induces cerebellar ataxia

SK3-1C, a Dominant-negative Suppressor of SKCa and IKCa Channels

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