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

Many ion channels and receptors display striking phenotypes for gain-of-fun ction mutations but milder phenotypes for null mutations. Gain of molecular function can have several mechanistic bases: selectivity changes, gating c hanges including constitutive activation and slowed inactivation, eliminati on of a subunit that enhances inactivation, decreased drug sensitivity, cha nges 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 cell ular and circuit level; of these syndromes, the cardiac long-QT syndromes a re explained in a more straightforward way than are the epilepsies. G prote in-coupled receptors are also affected by activating mutations.