Distinctive Role of KV1.1 Subunits in the Biology and Functions of Low Threshold K+ Channels with Implication for Neurological Disease

Saak  Ovsepian; Marie Le Berre; Volker Steuber; Valerie O'Leary; Christian Leibold; Oliver Dolly

doi:10.1016/j.pharmthera.2016.01.005

Distinctive Role of KV1.1 Subunits in the Biology and Functions of Low Threshold K+ Channels with Implication for Neurological Disease

Saak Ovsepian, Marie Le Berre, Volker Steuber, Valerie O'Leary, Christian Leibold, Oliver Dolly

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Abstract

The diversity of pore-forming subunits of K_V1 channels (K_V1.1–K_V1.8) affords their physiological versatility and predicts a range of functional impairments resulting from genetic aberrations. Curiously, identified so far human neurological conditions associated with dysfunctions of K_V1 channels have been linked exclusively to mutations in the KCNA1 gene encoding for the K_V1.1 subunit. The absence of phenotypes related to irregularities in other subunits, including the prevalent K_V1.2 subunit of neurons is highly perplexing given that deletion of the corresponding kcna2 gene in mouse models precipitates symptoms reminiscent to those of K_V1.1 knockouts. Herein, we critically evaluate the molecular and biophysical characteristics of the K_V1.1 protein in comparison with others and discuss their role in the greater penetrance of KCNA1 mutations in humans leading to the neurological signs of episodic ataxia type 1 (EA1). Future research and interpretation of emerging data should afford new insights towards a better understanding of the role of K_V1.1 in integrative mechanisms of neurons and synaptic functions under normal and disease conditions

Original language	English
Pages (from-to)	93-101
Journal	Pharmacology & Therapeutics
Volume	159
Early online date	26 Jan 2016
DOIs	https://doi.org/10.1016/j.pharmthera.2016.01.005
Publication status	Published - 1 Mar 2016

Keywords

KCNA1
low-threshold potassium channel
Hetero-tetramer
Dendrotoxin-K
Synaptic integration
Episodic ataxia

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10.1016/j.pharmthera.2016.01.005

Accepted ManuscriptAccepted author manuscript, 681 KBLicence: CC BY-NC-ND

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title = "Distinctive Role of KV1.1 Subunits in the Biology and Functions of Low Threshold K+ Channels with Implication for Neurological Disease",

abstract = " The diversity of pore-forming subunits of KV1 channels (KV1.1–KV1.8) affords their physiological versatility and predicts a range of functional impairments resulting from genetic aberrations. Curiously, identified so far human neurological conditions associated with dysfunctions of KV1 channels have been linked exclusively to mutations in the KCNA1 gene encoding for the KV1.1 subunit. The absence of phenotypes related to irregularities in other subunits, including the prevalent KV1.2 subunit of neurons is highly perplexing given that deletion of the corresponding kcna2 gene in mouse models precipitates symptoms reminiscent to those of KV1.1 knockouts. Herein, we critically evaluate the molecular and biophysical characteristics of the KV1.1 protein in comparison with others and discuss their role in the greater penetrance of KCNA1 mutations in humans leading to the neurological signs of episodic ataxia type 1 (EA1). Future research and interpretation of emerging data should afford new insights towards a better understanding of the role of KV1.1 in integrative mechanisms of neurons and synaptic functions under normal and disease conditions",

keywords = "KCNA1, low-threshold potassium channel, Hetero-tetramer, Dendrotoxin-K, Synaptic integration, Episodic ataxia",

author = "Saak Ovsepian and {Le Berre}, Marie and Volker Steuber and Valerie O'Leary and Christian Leibold and Oliver Dolly",

note = "This document is the Accepted Manuscript version of the following article: Saak V. Ovsepian; Marie LeBerre; Volker Steuber; Valerie B. O{\textquoteright}Leary; Christian Leibold; & J. Oliver Dolly; {\textquoteleft}Distinctive role of KV1.1 subunit in the biology and functions of low threshold K+ channels with implications for neurological disease{\textquoteright}, Pharmacology & Therapeutics, Vol. 159, March 2016, pp. 93-101. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ The version of record is available on line at doi: http:dx.doi.org/10.1016/j.pharmthera.2016.01.005 {\textcopyright} 2016 Elsevier Inc. All rights reserved. ",

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AU - Ovsepian, Saak

AU - Le Berre, Marie

AU - Steuber, Volker

AU - O'Leary, Valerie

AU - Leibold, Christian

AU - Dolly, Oliver

N1 - This document is the Accepted Manuscript version of the following article: Saak V. Ovsepian; Marie LeBerre; Volker Steuber; Valerie B. O’Leary; Christian Leibold; & J. Oliver Dolly; ‘Distinctive role of KV1.1 subunit in the biology and functions of low threshold K+ channels with implications for neurological disease’, Pharmacology & Therapeutics, Vol. 159, March 2016, pp. 93-101. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ The version of record is available on line at doi: http:dx.doi.org/10.1016/j.pharmthera.2016.01.005 © 2016 Elsevier Inc. All rights reserved.

PY - 2016/3/1

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N2 - The diversity of pore-forming subunits of KV1 channels (KV1.1–KV1.8) affords their physiological versatility and predicts a range of functional impairments resulting from genetic aberrations. Curiously, identified so far human neurological conditions associated with dysfunctions of KV1 channels have been linked exclusively to mutations in the KCNA1 gene encoding for the KV1.1 subunit. The absence of phenotypes related to irregularities in other subunits, including the prevalent KV1.2 subunit of neurons is highly perplexing given that deletion of the corresponding kcna2 gene in mouse models precipitates symptoms reminiscent to those of KV1.1 knockouts. Herein, we critically evaluate the molecular and biophysical characteristics of the KV1.1 protein in comparison with others and discuss their role in the greater penetrance of KCNA1 mutations in humans leading to the neurological signs of episodic ataxia type 1 (EA1). Future research and interpretation of emerging data should afford new insights towards a better understanding of the role of KV1.1 in integrative mechanisms of neurons and synaptic functions under normal and disease conditions

AB - The diversity of pore-forming subunits of KV1 channels (KV1.1–KV1.8) affords their physiological versatility and predicts a range of functional impairments resulting from genetic aberrations. Curiously, identified so far human neurological conditions associated with dysfunctions of KV1 channels have been linked exclusively to mutations in the KCNA1 gene encoding for the KV1.1 subunit. The absence of phenotypes related to irregularities in other subunits, including the prevalent KV1.2 subunit of neurons is highly perplexing given that deletion of the corresponding kcna2 gene in mouse models precipitates symptoms reminiscent to those of KV1.1 knockouts. Herein, we critically evaluate the molecular and biophysical characteristics of the KV1.1 protein in comparison with others and discuss their role in the greater penetrance of KCNA1 mutations in humans leading to the neurological signs of episodic ataxia type 1 (EA1). Future research and interpretation of emerging data should afford new insights towards a better understanding of the role of KV1.1 in integrative mechanisms of neurons and synaptic functions under normal and disease conditions

KW - KCNA1

KW - low-threshold potassium channel

KW - Hetero-tetramer

KW - Dendrotoxin-K

KW - Synaptic integration

KW - Episodic ataxia

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DO - 10.1016/j.pharmthera.2016.01.005

M3 - Article

SN - 0163-7258

VL - 159

SP - 93

EP - 101

JO - Pharmacology & Therapeutics

JF - Pharmacology & Therapeutics

ER -

Distinctive Role of KV1.1 Subunits in the Biology and Functions of Low Threshold K+ Channels with Implication for Neurological Disease

Abstract

Keywords

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