Neuronal KCNQ potassium channels:physislogy and role in disease

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Abstract

Humans have over 70 potassium channel genes, but only some of these have been linked to disease. In this respect, the KCNQ family of potassium channels is exceptional: mutations in four out of five KCNQ genes underlie diseases including cardiac arrhythmias, deafness and epilepsy. These disorders illustrate the different physiological functions of KCNQ channels, and provide a model for the study of the 'safety margin' that separates normal from pathological levels of channel expression. In addition, several KCNQ isoforms can associate to form heteromeric channels that underlie the M-current, an important regulator of neuronal excitability.

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Most cited references 79

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Prestin is the motor protein of cochlear outer hair cells.

J Zheng, W. Shen, D He … (2000)

The outer and inner hair cells of the mammalian cochlea perform different functions. In response to changes in membrane potential, the cylindrical outer hair cell rapidly alters its length and stiffness. These mechanical changes, driven by putative molecular motors, are assumed to produce amplification of vibrations in the cochlea that are transduced by inner hair cells. Here we have identified an abundant complementary DNA from a gene, designated Prestin, which is specifically expressed in outer hair cells. Regions of the encoded protein show moderate sequence similarity to pendrin and related sulphate/anion transport proteins. Voltage-induced shape changes can be elicited in cultured human kidney cells that express prestin. The mechanical response of outer hair cells to voltage change is accompanied by a 'gating current', which is manifested as nonlinear capacitance. We also demonstrate this nonlinear capacitance in transfected kidney cells. We conclude that prestin is the motor protein of the cochlear outer hair cell.

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Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.

D P Kelsell, J Dunlop, H P Stevens … (1997)

Severe deafness or hearing impairment is the most prevalent inherited sensory disorder, affecting about 1 in 1,000 children. Most deafness results from peripheral auditory defects that occur as a consequence of either conductive (outer or middle ear) or sensorineuronal (cochlea) abnormalities. Although a number of mutant genes have been identified that are responsible for syndromic (multiple phenotypic disease) deafness such as Waardenburg syndrome and Usher 1B syndrome, little is known about the genetic basis of non-syndromic (single phenotypic disease) deafness. Here we study a pedigree containing cases of autosomal dominant deafness and have identified a mutation in the gene encoding the gap-junction protein connexin 26 (Cx26) that segregates with the profound deafness in the family. Cx26 mutations resulting in premature stop codons were also found in three autosomal recessive non-syndromic sensorineuronal deafness pedigrees, genetically linked to chromosome 13q11-12 (DFNB1), where the Cx26 gene is localized. Immunohistochemical staining of human cochlear cells for Cx26 demonstrated high levels of expression. To our knowledge, this is the first non-syndromic sensorineural autosomal deafness susceptibility gene to be identified, which implicates Cx26 as an important component of the human cochlea.

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A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns.

N. Singh, C Charlier, D. Stauffer … (1998)

Idiopathic generalized epilepsies account for about 40% of epilepsy up to age 40 and commonly have a genetic basis. One type is benign familial neonatal convulsions (BFNC), a dominantly inherited disorder of newborns. We have identified a sub-microscopic deletion of chromosome 20q13.3 that co-segregates with seizures in a BFNC family. Characterization of cDNAs spanning the deleted region identified one encoding a novel voltage-gated potassium channel, KCNQ2, which belongs to a new KQT-like class of potassium channels. Five other BFNC probands were shown to have KCNQ2 mutations, including two transmembrane missense mutations, two frameshifts and one splice-site mutation. This finding in BFNC provides additional evidence that defects in potassium channels are involved in the mammalian epilepsy phenotype.

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Author and article information

Journal

Title: Nature Reviews Neuroscience

Abbreviated Title: Nat Rev Neurosci

Publisher: Springer Science and Business Media LLC

ISSN (Print): 1471-003X

ISSN (Electronic): 1471-0048

Publication date Created: October 2000

Publication date (Print): October 2000

Volume: 1

Issue: 1

Pages: 21-30

Article

DOI: 10.1038/35036198

PubMed ID: 11252765

SO-VID: bd338f30-1921-488b-92d7-5b4600860900

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Neuronal KCNQ potassium channels:physislogy and role in disease

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Neuronal Signaling

Most cited references 79

Prestin is the motor protein of cochlear outer hair cells.

Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.

A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns.

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