Neuronal KCNQ potassium channels:physislogy and role in disease

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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Figure 1: The structure of KCNQ channels.
Figure 2: KCNQ2/KCNQ3 heteromers yield currents with the properties of the M-current.
Figure 3: Inhibition of neuronal M-currents leads to hyperexcitability.
Figure 4: Potassium recycling in the scala media of the inner ear.

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Acknowledgements

Work in my laboratory is supported by the Deutsche Forschungsgemeinschaft, the European Community, the Fonds der Chemischen Industrie and the Louis-Jeantet Prize for Medicine.

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DATABASE LINKS

KCNQ1

LQTS

JLNS

KCNE1

KCNE3

KCNQ2

KCNQ3

BFNC

KCNQ5

KCNQ4

DFNA2

connexin 26

connexin 30

connexin 31

connexin 32

FURTHER INFORMATION

Potassium channel nomenclature

Thomas Jentsch's laboratory

ENCYCLOPEDIA OF LIFE SCIENCES

Hair cells

Glossary

SPLICE VARIANTS

Further forms of a protein derived from alternative processing of its mRNA.

HETEROMERS

Channels formed by the assembly of two or more different subunits.

HOMOMERIC CHANNELS

Channels formed by several copies of a single subunit.

POSITIONAL CLONING

A strategy for identifying a gene associated with a genetic disease in which the phenotype is correlated with a chromosomal site and the DNA cloned and compared with that in normal individuals.

DOMINANT NEGATIVE

A mutant protein that interacts with the normal form and blocks its function.

NOISE ANALYSIS

A technique in which the random fluctuations in membrane potential are used to give information on the properties of single channels.

MISSENSE MUTATION

A mutation in which an incorrect amino acid is incorporated into the protein.

FRAME-SHIFT MUTATION

The addition or deletion of a nucleotide such that the protein sequence from that point onwards is altered.

SPLICE-SITE MUTATION

A mutation at the site where the mRNA is processed to generate protein variants.

HAPLOINSUFFICIENCY

Loss of one copy (one allele) of a gene is sufficient to give rise to disease. Haploinsufficiency implies that no dominant-negative effect of the mutated gene product has to be invoked.

POLYGENIC

A characteristic controlled by different genes, each of which have only a small role in the phenotype.

STRIA VASCULARIS

The lateral part of the scala media, which contains the epithelia that secrete the endolymph.

ORGAN OF CORTI

The primary sensory organ of hearing. It is located on the floor of the scala media, and consists of sensory hair cells (one row of inner hair cells and three rows of outer hair cells) and supporting cells. The stereocilia of the hair cells touch the gelatinous tectorial membrane, which covers the organ.

ENDOLYMPH

The fluid filling the scala media of the cochlea and the cavities of the vestibular organ. In contrast to the perilymph, which fills the scala tympani and scala vestibuli, it has an unusual ion composition with a high potassium concentration.

SCALA MEDIA

The central cavity of the cochlea that is sandwiched between the scala vestibuli (which receives acoustic input through the ossicles of the middle ear) and the scala tympani. It is filled with endolymph and contains the organ of Corti.

GAP JUNCTIONS

Channels that connect adjacent cells and allow for the free passage of small molecules. They are formed by proteins called connexins.

GENE DOSAGE

The number of times a gene appears in the genome.

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Jentsch, T. Neuronal KCNQ potassium channels:physislogy and role in disease. Nat Rev Neurosci 1, 21–30 (2000). https://doi.org/10.1038/35036198

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