Pleiotropic effects of a disrupted K<sup>+</sup>channel gene: Reduced body weight, impaired motor skill and muscle contraction, but no seizures

Ho, Chi Shun; Grange, Robert W.; Joho, Rolf H.

doi:10.1073/pnas.94.4.1533

Cited by 102 publications

(104 citation statements)

References 19 publications

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“…It is possible that the afterhyperpolarization in the Kv3.1Ϫ/Ϫ mice reflects a compensatory increase in lowthreshold current in these animals. Combined with previous work demonstrating the loss of Kv3.1 mRNA and protein in the Kv3.1Ϫ/Ϫ mice (Ho et al, 1997), our findings strongly support the identification of the I HT current recorded at the somata of MNTB neurons with the Kv3.1 channel.…”

Section: Contribution Of Kv31 To the Firing Pattern Of Mntb Neuronssupporting

confidence: 69%

“…The Kv3.1 gene was mutated by homologous recombination by a replacement vector as previously described in 129/Sv mice (Ho et al, 1997). Briefly, the coding region between EcoRI and MscI (35 bp in the S2-S3 linker) was replaced with a neomycinresistant cassette.…”

Section: Methodsmentioning

confidence: 99%

“…We first tested the role of the Kv3.1 channel in MNTB neurons by comparing the properties of MNTB neurons in 9-to 14-d-old brainstem slices from wild-type mice with those in which the Kv3.1 gene had been deleted by homologous recombination (Ho et al, 1997). As described previously, wild-type mice express a high-threshold potassium current I HT whose properties closely match those of Kv3.1 in transfected cell lines (Wang et al, 1998).…”

Section: Contribution Of Kv31 To the Firing Pattern Of Mntb Neuronsmentioning

confidence: 99%

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Modulation of the Kv3.1b Potassium Channel Isoform Adjusts the Fidelity of the Firing Pattern of Auditory Neurons

et al. 2003

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Neurons of the medial nucleus of the trapezoid body, which transmit auditory information that is used to compute the location of sounds in space, are capable of firing at high frequencies with great temporal precision. We found that elimination of the Kv3.1 gene in mice results in the loss of a high-threshold component of potassium current and failure of the neurons to follow high-frequency stimulation. A partial decrease in Kv3.1 current can be produced in wild-type neurons of the medial nucleus of the trapezoid body by activation of protein kinase C. Paradoxically, activation of protein kinase C increases temporal fidelity and the number of action potentials that are evoked by intermediate frequencies of stimulation. Computer simulations confirm that a partial decrease in Kv3.1 current is sufficient to increase the accuracy of response at intermediate frequencies while impairing responses at high frequencies. We further establish that, of the two isoforms of the Kv3.1 potassium channel that are expressed in these neurons, Kv3.1a and Kv3.1b, the decrease in Kv3.1 current is mediated by selective phosphorylation of the Kv3.1b isoform. Using site-directed mutagenesis, we identify a specific C-terminal phosphorylation site responsible for the observed difference in response of the two isoforms to protein kinase C activation. Our results suggest that modulation of Kv3.1 by phosphorylation allows auditory neurons to tune their responses to different patterns of sensory stimulation.

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Section: Contribution Of Kv31 To the Firing Pattern Of Mntb Neuronssupporting

confidence: 69%

Section: Methodsmentioning

confidence: 99%

Section: Contribution Of Kv31 To the Firing Pattern Of Mntb Neuronsmentioning

confidence: 99%

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Modulation of the Kv3.1b Potassium Channel Isoform Adjusts the Fidelity of the Firing Pattern of Auditory Neurons

et al. 2003

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“…17 The times that the animals were able to stay on the rod were recorded. Immediately after falling the animals received an electrical shock (1 s, 0.8 mA).…”

Section: Rotarodmentioning

confidence: 99%

Demyelination but no cognitive, motor or behavioral deficits after adenovirus-mediated gene transfer into the brain

Fathallah‐Shaykh

Zhao

et al. 2000

Gene Ther

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Adenovirus-mediated gene transfer of interferon gamma (AdIFN) elicits rejection of intracerebral Lewis lung carcinoma. In this system, gene transfer into brain parenchymal cells is both necessary and sufficient to generate the antitumor response. Despite persistent parenchymal inflammation and demyelination, wild-type mice injected intracerebrally with either AdIFN or ␤-galactosidase adenovirus (AdBGAL) perform as well as non-injected animals in behavioral, memory, and motor tests. Both AdIFN and

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“…The generation and initial characterization of mice lacking Kv3.1 and Kv3.3 K ϩ channels has been described previously (Ho et al, 1997;Espinosa et al, 2001Espinosa et al, , 2004Joho et al, 2006a). Mice were kept on a 12 h light/dark cycle, and all behavioral experiments were performed with age-matched mice (ϳ3-6 months of age) derived on a mixed genetic background (ϳ25% of the genome was derived from 129/SvJ, ϳ25% from C57BL/6, and ϳ50% from ICR).…”

Section: Methodsmentioning

confidence: 99%

Purkinje-Cell-Restricted Restoration of Kv3.3 Function Restores Complex Spikes and Rescues Motor Coordination inKcnc3Mutants

Hurlock

McMahon²,

Joho³

2008

J. Neurosci.

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The fast-activating/deactivating voltage-gated potassium channel Kv3.3 (Kcnc3) is expressed in various neuronal cell types involved in motor function, including cerebellar Purkinje cells. Spinocerebellar ataxia type 13 (SCA13) patients carrying dominant-negative mutations in Kcnc3 and Kcnc3-null mutant mice both display motor incoordination, suggested in mice by increased lateral deviation while ambulating and slips on a narrow beam. Motor skill learning, however, is spared. Mice lacking Kcnc3 also exhibit muscle twitches. In addition to broadened spikes, recordings of Kcnc3-null Purkinje cells revealed fewer spikelets in complex spikes and a lower intraburst frequency. Targeted reexpression of Kv3.3 channels exclusively in Purkinje cells in Kcnc3-null mice as well as in mice also heterozygous for Kv3.1 sufficed to restore simple spike brevity along with normal complex spikes and to rescue specifically coordination. Therefore, spike parameters requiring Kv3.3 function in Purkinje cells are involved in the ataxic null phenotype and motor coordination, but not motor learning.Key words: K channels; burst firing; motor dysfunction; cerebellum; Purkinje cell; complex spike IntroductionVoltage-gated potassium (Kv) channels of the Kv3 subfamily enable neurons to fire narrow action potentials at high frequencies beyond ϳ200 Hz. Four separate genes (Kcnc1-Kcnc4 ) encoding subunits Kv3.1-Kv3.4 are expressed in various combinations in CNS neurons in which they assemble into homotetrameric and heterotetrameric channels. Mice lacking the Kcnc3-encoded Kv3.3 subunit exhibit motor deficits manifested as increased lateral deviation while ambulating and increased slips while traversing a narrow beam (McMahon et al., 2004;Joho et al., 2006b). A role for Kv3.3 channels in motor coordination is also underscored by the recent finding that dominant-negative mutations found in the human KCNC3 gene correlate with the neurological disorder spinocerebellar ataxia 13 (Waters et al., 2006). Kv3-type channels are distinguished by exceptionally rapid kinetics of activation and deactivation, rendering them ideally suited to drive repolarization that is rapid, both in its onset and relief, so that the next action potential upstroke can occur with minimal delay in the absence of lingering afterhyperpolarization. High-frequency spiking is facilitated by both minimizing sodium channel inactivation through brief action potentials and by promoting sodium channel deinactivation through the excursion to negative potentials during the fast afterhyperpolarization. Indeed, the loss of Kv3-type channels results in broadened spikes accompanied by decelerated firing (Rudy and McBain, 2001). Unlike most other neuron types in which Kv3.3 subunits are expressed with other Kv3-type subunits, Purkinje cells express high levels of Kv3.3 and lower levels of Kv3.4 (Weiser et al., 1994;Martina et al., 2003). Loss of Kv3.3 results in a doubling of action potential duration (McMahon et al., 2004). Furthermore, blockade with tetraethylammonium (TEA) or BDS-I at a conc...

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Pleiotropic effects of a disrupted K⁺channel gene: Reduced body weight, impaired motor skill and muscle contraction, but no seizures

Abstract: To investigate the roles of K ؉ channels in the regulation and fine-tuning of cellular excitability, we generated a mutant mouse carrying a disrupted gene for the fast activating, voltage-gated K ؉ channel Kv3.1. Kv3

Cited by 102 publications

References 19 publications

Modulation of the Kv3.1b Potassium Channel Isoform Adjusts the Fidelity of the Firing Pattern of Auditory Neurons

Modulation of the Kv3.1b Potassium Channel Isoform Adjusts the Fidelity of the Firing Pattern of Auditory Neurons

Demyelination but no cognitive, motor or behavioral deficits after adenovirus-mediated gene transfer into the brain

Purkinje-Cell-Restricted Restoration of Kv3.3 Function Restores Complex Spikes and Rescues Motor Coordination inKcnc3Mutants

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Pleiotropic effects of a disrupted K+channel gene: Reduced body weight, impaired motor skill and muscle contraction, but no seizures

Abstract: To investigate the roles of K ؉ channels in the regulation and fine-tuning of cellular excitability, we generated a mutant mouse carrying a disrupted gene for the fast activating, voltage-gated K ؉ channel Kv3.1. Kv3

Cited by 102 publications

References 19 publications

Modulation of the Kv3.1b Potassium Channel Isoform Adjusts the Fidelity of the Firing Pattern of Auditory Neurons

Modulation of the Kv3.1b Potassium Channel Isoform Adjusts the Fidelity of the Firing Pattern of Auditory Neurons

Demyelination but no cognitive, motor or behavioral deficits after adenovirus-mediated gene transfer into the brain

Purkinje-Cell-Restricted Restoration of Kv3.3 Function Restores Complex Spikes and Rescues Motor Coordination inKcnc3Mutants

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Pleiotropic effects of a disrupted K⁺channel gene: Reduced body weight, impaired motor skill and muscle contraction, but no seizures