Nervous system KV7 disorders: breakdown of a subthreshold brake
Voltage-gated K + channels of the K V 7 (KCNQ) family have been identified in the last 10â15 years by discovering the causative genes for three autosomal dominant diseases: cardiac arrhythmia (long QT syndrome) with or without congenital deafness ( KCNQ1 ), a neonatal epilepsy ( KCNQ2 and KCNQ3 )...
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Published in | The Journal of physiology Vol. 586; no. 7; pp. 1791 - 1801 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
Oxford, UK
The Physiological Society
01.04.2008
Blackwell Publishing Ltd Blackwell Science Inc |
Subjects | |
Online Access | Get full text |
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Summary: | Voltage-gated K + channels of the K V 7 (KCNQ) family have been identified in the last 10â15 years by discovering the causative genes for three autosomal dominant
diseases: cardiac arrhythmia (long QT syndrome) with or without congenital deafness ( KCNQ1 ), a neonatal epilepsy ( KCNQ2 and KCNQ3 ) and progressive deafness alone ( KCNQ4 ). A fifth member of this gene family ( KCNQ5 ) is not affected in a disease so far. Four genes ( KCNQ2â5 ) are expressed in the nervous system. This review is focused on recent findings on the neuronal K V 7 channelopathies, in particular on benign familial neonatal seizures (BFNS) and peripheral nerve hyperexcitability (PNH,
neuromyotonia, myokymia) caused by KCNQ2 mutations. The phenotypic spectrum associated with KCNQ2 mutations is probably broader than initially thought, as patients with severe epilepsies and developmental delay, or with
Rolando epilepsy have been described. With regard to the underlying molecular pathophysiology, it has been shown that mutations
with very subtle changes restricted to subthreshold voltages can cause BFNS thereby proving in a human disease model that
this is the relevant voltage range for these channels to modulate neuronal firing. The two mutations associated with PNH induce
much more severe channel dysfunction with a dominant negative effect on wild type (WT) channels. Finally, K V 7 channels present interesting targets for new therapeutic approaches to diseases caused by neuronal hyperexcitability, such
as epilepsy, neuropathic pain, and migraine. The molecular mechanism of K V 7 activation by retigabine, which is in phase III clinical testing to treat pharmacoresistant focal epilepsies, has been recently
elucidated as a stabilization of the open conformation by binding to the pore region. |
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Bibliography: | S. Maljevic and T. V. Wuttke contributed equally and are listed in alphabetical order. This report was presented at a symposium on Kv7 (KCNQ) potassium channels that are mutated in human diseases, held at a joint meeting of The Slovak Physiological Society, The Physiological Society and The Federation of European Physiological Societies in Bratislava, Slovakia on 14 September 2007. It was commissioned by the Editorial Board and reflects the views of the authors. ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 ObjectType-Review-3 content type line 23 ObjectType-Feature-3 ObjectType-Review-1 |
ISSN: | 0022-3751 1469-7793 |
DOI: | 10.1113/jphysiol.2008.150656 |