Alternative Splicing Regulates Kv3.1 Polarized Targeting to Adjust Maximal Spiking Frequency

Gu, Yuanzheng; Barry, Joshua; McDougel, Robert; Terman, David; Gu, Chen

doi:10.1074/jbc.m111.299305

Cited by 39 publications

(55 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However we found that spatial segregation of nodal Na + and Kv3.1 channels or juxtaparanodal Kv1.1 channels had a minimal impact on AN conduction velocity. Axonal targeting of Kv3.1 channels is critical to enable neurons to fire action potentials at the maximal frequency (Gu et al, 2012). Our study further suggests that the re-localization of Kv3.1 channels is unlikely to affect action potential firing frequency during AN dys-myelination.…”

Section: Discussionmentioning

confidence: 99%

Computational modeling of the effects of auditory nerve dysmyelination

Brown

Hamann

2014

Front. Neuroanat.

View full text Add to dashboard Cite

Our previous study showed that exposure to loud sound leading to hearing loss elongated the auditory nerve (AN) nodes of Ranvier and triggered notable morphological changes at paranodes and juxtaparanodes. Here we used computational modeling to examine how theoretical redistribution of voltage gated Na+, Kv3.1, and Kv1.1 channels along the AN may be responsible for the alterations of conduction property following acoustic over-exposure. Our modeling study infers that changes related to Na+ channel density (rather than the redistribution of voltage gated Na+, Kv3.1, and Kv1.1 channels) is the likely cause of the decreased conduction velocity and the conduction block observed after acoustic overexposure (AOE).

show abstract

Section: Discussionmentioning

confidence: 99%

Computational modeling of the effects of auditory nerve dysmyelination

Brown

Hamann

2014

Front. Neuroanat.

View full text Add to dashboard Cite

show abstract

“…The K V 3 family contains four members, K V 3.1-K V 3.4. K V 3.1 is a fast-activating/ fast-deactivating channel that regulates spike frequency in several brain regions (22)(23)(24). When expressed heterologously in mammalian cells, Na V β1 had no effect on activation kinetics, voltage dependence of activation or deactivation of K V 3.1 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Modulation of voltage-gated K ⁺ channels by the sodium channel β1 subunit

Nguyen¹,

Miyazaki

Hoshi³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Voltage-gated sodium (Na V ) and potassium (K V ) channels are critical components of neuronal action potential generation and propagation. Here, we report that Na V β1 encoded by SCN1b, an integral subunit of Na V channels, coassembles with and modulates the biophysical properties of K V 1 and K V 7 channels, but not K V 3 channels, in an isoform-specific manner. Distinct domains of Na V β1 are involved in modulation of the different K V channels. Studies with channel chimeras demonstrate that Na V β1-mediated changes in activation kinetics and voltage dependence of activation require interaction of Na V β1 with the channel's voltage-sensing domain, whereas changes in inactivation and deactivation require interaction with the channel's pore domain. A molecular model based on docking studies shows Na V β1 lying in the crevice between the voltage-sensing and pore domains of K V channels, making significant contacts with the S1 and S5 segments. Cross-modulation of Na V and K V channels by Na V β1 may promote diversity and flexibility in the overall control of cellular excitability and signaling. voltage-gated sodium (Na V ) and potassium (K V ) channels mediate the depolarization phase (1) and repolarization phase (2, 3), respectively, of neuronal action potentials. Although intrinsic domains within the Na V α subunits underlie voltage-dependent gating properties and sodium-specific permeation, five Na V β subunits (β1, β1B, β2, β3, β4) assemble with and modulate inactivation kinetics and the voltage dependence of activation and inactivation of Na V α subunits (1, 4). In addition, these Na V β subunits function in cell adhesion and contribute to neuronal migration, pathfinding, and fasciculation (4-8). Given their ubiquitous roles and distribution in the CNS, Na V β subunits play a major role in fine-tuning of action potential generation, propagation, and frequency. Subtle changes to their function have resulted in a range of detrimental neurological diseases in humans such as genetic epilepsy with febrile seizures plus (GEFS+), Dravet syndrome (severe myoclonic epilepsy of infancy), temporal lobe epilepsy, febrile seizures, and decreased responsiveness to the anticonvulsant drugs carbamazepine and phenytoin (7-12).K V channels are important contributors to action potential repolarization. K V channels in mammals are encoded by 40 genes grouped into 12 subfamilies (K V 1-K V 12). Na V β1, which was previously thought to be specific for Na V channels, was recently shown to coassemble with and modulate the properties of the K V 4.x subfamily of channels (13-15). In the rodent heart, Na V β1 coprecipitates with K V 4.3, and in heterologous expression systems it increases the amplitude of the K V 4.3 current and speeds up activation (14, 15). In the rodent brain, Na V β1 coprecipitates with K V 4.2, and in heterologous expression systems it enhances surface expression of the channel and increases current amplitude (13). Genetic knockout of Na V β1 in mice prolongs action potential firing in pyramidal neurons through i...

show abstract

“…2008, Gu et al . 2012, Yanagi et al . 2014), and the voltage‐activated sodium Nav1.1 channels that have recently been suggested as a therapeutic target for cognitive disorders in schizophrenia (Jensen et al .…”

mentioning

confidence: 99%

The translationally relevant mouse model of the 15q13.3 microdeletion syndrome reveals deficits in neuronal spike firing matching clinical neurophysiological biomarkers seen in schizophrenia

et al. 2016

View full text Add to dashboard Cite

AimTo date, the understanding and development of novel treatments for mental illness is hampered by inadequate animal models. For instance, it is unclear to what extent commonly used behavioural tests in animals can inform us on the mental and affective aspects of schizophrenia.MethodsTo link pathophysiological processes in an animal model to clinical findings, we have here utilized the recently developed Df(h15q13)/+ mouse model for detailed investigations of cortical neuronal engagement during pre‐attentive processing of auditory information from two back‐translational auditory paradigms. We also investigate if compromised putative fast‐spiking interneurone (FSI) function can be restored through pharmacological intervention using the Kv3.1 channel opener RE1. Chronic multi‐array electrodes in primary auditory cortex were used to record single cell firing from putative pyramidal and FSI in awake animals during processing of auditory sensory information.ResultsWe find a decreased amplitude in the response to auditory stimuli and reduced recruitment of neurones to fast steady‐state gamma oscillatory activity. These results resemble encephalography recordings in patients with schizophrenia. Furthermore, the probability of interneurones to fire with low interspike intervals during 80 Hz auditory stimulation was reduced in Df(h15q13)/+ mice, an effect that was partially reversed by the Kv3.1 channel modulator, RE1.ConclusionThis study offers insight into the consequences on a neuronal level of carrying the 15q13.3 microdeletion. Furthermore, it points to deficient functioning of interneurones as a potential pathophysiological mechanism in schizophrenia and suggests a therapeutic potential of Kv3.1 channel openers.

show abstract

Alternative Splicing Regulates Kv3.1 Polarized Targeting to Adjust Maximal Spiking Frequency

Cited by 39 publications

References 64 publications

Computational modeling of the effects of auditory nerve dysmyelination

Computational modeling of the effects of auditory nerve dysmyelination

Modulation of voltage-gated K ⁺ channels by the sodium channel β1 subunit

The translationally relevant mouse model of the 15q13.3 microdeletion syndrome reveals deficits in neuronal spike firing matching clinical neurophysiological biomarkers seen in schizophrenia

Contact Info

Product

Resources

About

Alternative Splicing Regulates Kv3.1 Polarized Targeting to Adjust Maximal Spiking Frequency

Cited by 39 publications

References 64 publications

Computational modeling of the effects of auditory nerve dysmyelination

Computational modeling of the effects of auditory nerve dysmyelination

Modulation of voltage-gated K + channels by the sodium channel β1 subunit

The translationally relevant mouse model of the 15q13.3 microdeletion syndrome reveals deficits in neuronal spike firing matching clinical neurophysiological biomarkers seen in schizophrenia

Contact Info

Product

Resources

About

Modulation of voltage-gated K ⁺ channels by the sodium channel β1 subunit