Human GABAA g2 -- Lys 289
This mutation has been correlated with childhood absence epilepsy and febrile seizures.
The GABA EC50 did not change with this mutation. Diazepam enhanced a1b3g2L(K289M) GABAA receptor currents and this was not different from that observed for wild-type a1b3g2L.
The mean peak amplitude of currents mediated by a1b3g2L(K289M) receptors was not significantly different from the mean amplitude of currents mediated by wild-type receptors. The a1b3g2L(K289M) currents deactivated significantly faster than either the a1b3g2L or the a1b3g2L(R43Q) currents.
The single channel conductance was unaltered. The duration of GABA-activated single channel openings mediated by a1b3g2L(K289M) receptors were shorter than those mediated by either a1b3g2L or a1b3g2L(R43Q) receptors.
Macdonald RL, Bianch MT, Feng H (2003) Mutations Linked to Generalized epilepsy in Humans Reduce GABAA Receptor Current. Experimental Neurology 184: S58-S67
Bianchi MT, Luyan S, Zhang H, Macdonald RL (2002) Two Different Mechanisms of Disinhibition Produced by GABAA Receptor Mutations Linked to Epilepsy in Humans The Journal of Neuroscience 22(12):5321-5327
Using a slower method of agonist application (cell-flow technique involving uncaging of caged GABA) than used by Bianchi et al., 2002, Ramakrishna and Hess examined the effects of the K289M mutation on GABA-activated currents and their modulation by diazepam. Using this approach the maximum GABA-activated current amplitude was significantly lower with the mutation. The GABA-induced current was enhanced by the addition of 10mM diazepam. The dissociation constants for the wild-type and mutated receptors were similar. The channel opening equilibrium constant and the rate constant for channel opening were both significantly lower for the mutant receptor compared to the wild-type receptor.
Ramakrishnan L, Hess GP (2004) On the Mechanism of a Mutated and Abnormally Functioning g-Amniobutyric Acid (A) Receptor Linked to Epilepsy. Biochemistry 43:7534-7540
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