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Published March 2000 | Published
Journal Article Open

Gain of function mutants: Ion channels and G protein-coupled receptors

Abstract

Many ion channels and receptors display striking phenotypes for gain-of-function mutations but milder phenotypes for null mutations. Gain of molecular function can have several mechanistic bases: selectivity changes, gating changes including constitutive activation and slowed inactivation, elimination of a subunit that enhances inactivation, decreased drug sensitivity, changes in regulation or trafficking of the channel, or induction of apoptosis. Decreased firing frequency can occur via increased function of K+ or Cl- channels. Channel mutants also cause gain-of-function syndromes at the cellular and circuit level; of these syndromes, the cardiac long-QT syndromes are explained in a more straightforward way than are the epilepsies. G protein-coupled receptors are also affected by activating mutations.

Additional Information

"Reprinted, with permission, from the Annual Review of Neuroscience, Volume 23 copyright 2000 by Annual Reviews, www.annualreviews.org" We thank A Auerbach, NJM Birdsall, J Garcia-Anoveros, R Dingledine, AG Engel, F Lehmann-Horn, D Mackinnon, JL Noebels, RL Ruff, M Sanguinetti, W Shi, M Yuzaki, and our colleagues at Caltech and Gottingen for many comments. Preparation of this chapter was supported by the Alexander von Humboldt Foundation. Work in our laboratories on this topic is supported by National Institutes of Health grants GM29836, MH49176, and NS11756, by the California Tobacco-Related Disease Research Program, and by the Sidney Stern Foundation.

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August 21, 2023
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