Gain of function mutants: ion channels and G protein-coupled receptors.
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.
Lester
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HA
Division of Biology, California Institute of Technology, Pasadena 91125, USA. Lester@caltech.edu
Karschin
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A
D000818:Animals; D018118:Chloride Channels / Q000235:genetics; D004827:Epilepsy / Q000235:genetics; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007473:Ion Channels / Q000235:genetics*; D008133:Long QT Syndrome / Q000235:genetics; D009154:Mutation / Q000502:physiology*; D015221:Potassium Channels / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics*
D018118:Chloride Channels; D007473:Ion Channels; D015221:Potassium Channels; D011956:Receptors, Cell Surface; D019204:GTP-Binding Proteins