Human GABA_A g2 -- Lys 289

hLys289Met

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) GABA_A 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 GABA_A Receptor Current. Experimental Neurology 184: S58-S67

Bianchi MT, Luyan S, Zhang H, Macdonald RL (2002) Two Different Mechanisms of Disinhibition Produced by GABA_A 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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