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J Physiol Volume 586, Number 7, 1791-1801, April 1, 2008 DOI: 10.1113/jphysiol.2008.150656
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SYMPOSIUM REPORT

Nervous system KV7 disorders: breakdown of a subthreshold brake

 Snezana Maljevic1, Thomas V. Wuttke1 and Holger Lerche1

1 Neurologische Klinik und Institut für Angewandte Physiologie, Universität Ulm, Ulm, Germany

Voltage-gated K+ channels of the KV7 (KCNQ) family have been identified in the last 10–15 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 (KCNQ2–5) are expressed in the nervous system. This review is focused on recent findings on the neuronal KV7 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, KV7 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 KV7 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.

(Received 2 January 2008; accepted after revision 31 January 2008; first published online 31 January 2008)
Corresponding author H. Lerche: Neurologische Klinik und Institut für Angewandte Physiologie, Universität Ulm, Zentrum Klinische Forschung, Helmholtzstr. 8/1, D-89081 Ulm, Germany. Email: holger.lerche{at}uni-ulm.de

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.

S. Maljevic and T. V. Wuttke contributed equally and are listed in alphabetical order.




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Kv7 (KCNQ) potassium channels that are mutated in human diseases
J. Physiol., April 1, 2008; 586(7): 1781 - 1783.
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