Kv3.3 potassium channels and spinocerebellar ataxia

Zhang, Yalan; Kaczmarek, Leonard K.

doi:10.1113/jp271343

Cited by 45 publications

(47 citation statements)

References 43 publications

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“…In the brain, particularly high levels of Kv3.3 mRNA and protein are found in Purkinje cells of the cerebellum and in brain stem nuclei, particularly in auditory circuits (28,35,77,136). As will be described later, human mutations in the gene for Kv3.3 (KCNC3) result in spinocerebellar ataxia type 13 (SCA13), a neurodegenerative disease that affects the cerebellum and is associated with abnormalities in the localization of sounds (160,245,260).…”

Section: Kv33bmentioning

confidence: 99%

Kv3 Channels: Enablers of Rapid Firing, Neurotransmitter Release, and Neuronal Endurance

Kaczmarek

Zhang

2017

Physiological Reviews

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143

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The intrinsic electrical characteristics of different types of neurons are shaped by the K channels they express. From among the more than 70 different K channel genes expressed in neurons, Kv3 family voltage-dependent K channels are uniquely associated with the ability of certain neurons to fire action potentials and to release neurotransmitter at high rates of up to 1,000 Hz. In general, the four Kv3 channels Kv3.1-Kv3.4 share the property of activating and deactivating rapidly at potentials more positive than other channels. Each Kv3 channel gene can generate multiple protein isoforms, which contribute to the high-frequency firing of neurons such as auditory brain stem neurons, fast-spiking GABAergic interneurons, and Purkinje cells of the cerebellum, and to regulation of neurotransmitter release at the terminals of many neurons. The different Kv3 channels have unique expression patterns and biophysical properties and are regulated in different ways by protein kinases. In this review, we cover the function, localization, and modulation of Kv3 channels and describe how levels and properties of the channels are altered by changes in ongoing neuronal activity. We also cover how the protein-protein interaction of these channels with other proteins affects neuronal functions, and how mutations or abnormal regulation of Kv3 channels are associated with neurological disorders such as ataxias, epilepsies, schizophrenia, and Alzheimer's disease.

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Section: Kv33bmentioning

confidence: 99%

Kv3 Channels: Enablers of Rapid Firing, Neurotransmitter Release, and Neuronal Endurance

Kaczmarek

Zhang

2017

Physiological Reviews

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143

180

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“…With these established genetic tools in hand we aimed to genetically model and monitor a human PC neurodegenerative disease in zebrafish. SCA13 is an autosomal dominant disease caused by a missense mutation allele of the KCNC3 gene encoding a voltage-dependent potassium channel KCNC3/Kv3.3 (Waters et al, 2006;Zhang and Kaczmarek, 2016). Fast firing neurons such as cerebellar PCs are crucially dependent on this channel as it mediates a rapid repolarization phase of an action potential, generating the repetitive spikelets of the complex spike (Kaczmarek and Zhang, 2017).…”

Section: Genetic Modeling Of a Pc Degeneration Disease In Zebrafishmentioning

confidence: 99%

Modeling Neurodegenerative Spinocerebellar Ataxia Type 13 in Zebrafish Using a Purkinje Neuron Specific Tunable Coexpression System

Namikawa¹,

Dorigo²,

Zagrebelsky

et al. 2019

J. Neurosci.

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Purkinje cells (PCs) are primarily affected in neurodegenerative spinocerebellar ataxias (SCAs). For generating animal models for SCAs, genetic regulatory elements specifically targeting PCs are required, thereby linking pathological molecular effects with impaired function and organismic behavior. Because cerebellar anatomy and function are evolutionary conserved, zebrafish represent an excellent model to study SCAs in vivo. We have isolated a 258 bp cross-species PC-specific enhancer element that can be used in a bidirectional manner for bioimaging of transgene-expressing PCs in zebrafish (both sexes) with variable copy numbers for tuning expression strength. Emerging ectopic expression at high copy numbers can be further eliminated by repurposing microRNA-mediated posttranslational mRNA regulation. Subsequently, we generated a transgenic SCA type 13 (SCA13) model, using a zebrafish-variant mimicking a human pathological SCA13 R420H mutation, resulting in cell-autonomous progressive PC degeneration linked to cerebellum-driven eye-movement deficits as observed in SCA patients. This underscores that investigating PC-specific cerebellar neuropathologies in zebrafish allows for interconnecting bioimaging of disease mechanisms with behavioral analysis suitable for therapeutic compound testing.

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“…Voltage‐gated potassium channels are important in setting membrane resting potential, regulating firing patterns and modifying action potential duration and neurotransmitter release . Mutations in genes encoding voltage‐gated potassium channels have been implicated in several conditions including spinocerebellar ataxia, paroxysmal movement disorders, and various epilepsies …”

Section: Introductionmentioning

confidence: 99%

Encephalopathies with KCNC1 variants: genotype‐phenotype‐functional correlations

Cameron

Maljevic

Nair

et al. 2019

Ann Clin Transl Neurol

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Objective To analyze clinical phenotypes associated with KCNC1 variants other than the Progressive Myoclonus Epilepsy‐causing variant p.Arg320His, determine the electrophysiological functional impact of identified variants and explore genotype‐phenotype‐physiological correlations. Methods Ten cases with putative pathogenic variants in KCNC1 were studied. Variants had been identified via whole‐exome sequencing or gene panel testing. Clinical phenotypic data were analyzed. To determine functional impact of variants detected in the Kv3.1 channel encoded by KCNC1, Xenopus laevis oocyte expression system and automated two‐electrode voltage clamping were used. Results Six unrelated patients had a Developmental and Epileptic Encephalopathy and a recurrent de novo variant p.Ala421Val (c.1262C > T). Functional analysis of p.Ala421Val revealed loss of function through a significant reduction in whole‐cell current, but no dominant‐negative effect. Three patients had a contrasting phenotype of Developmental Encephalopathy without seizures and different KCNC1 variants, all of which caused loss of function with reduced whole‐cell currents. Evaluation of the variant p.Ala513Val (c.1538C > T) in the tenth case, suggested it was a variant of uncertain significance. Interpretation These are the first reported cases of Developmental and Epileptic Encephalopathy due to KCNC1 mutation. The spectrum of phenotypes associated with KCNC1 is now broadened to include not only a Progressive Myoclonus Epilepsy, but an infantile onset Developmental and Epileptic Encephalopathy, as well as Developmental Encephalopathy without seizures. Loss of function is a key feature, but definitive electrophysiological separation of these phenotypes has not yet emerged.

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Kv3.3 potassium channels and spinocerebellar ataxia

Cited by 45 publications

References 43 publications

Kv3 Channels: Enablers of Rapid Firing, Neurotransmitter Release, and Neuronal Endurance

Kv3 Channels: Enablers of Rapid Firing, Neurotransmitter Release, and Neuronal Endurance

Modeling Neurodegenerative Spinocerebellar Ataxia Type 13 in Zebrafish Using a Purkinje Neuron Specific Tunable Coexpression System

Encephalopathies with KCNC1 variants: genotype‐phenotype‐functional correlations

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