Human GABA_A a1 -- Arg 58

mArg57Gln

This mutation has been correlated with Juvenile myoclinic epilepsy.

Cells expressing a1(Ala322Asp)b2g2 had smaller maximal GABA-activated currents than were seen in recordings from wild-type receptors. Diazepam potentiated GABA currents of both wildtype and mutant channels to a similar degree.

Cossette P, Liu L, Brisebois K, Dong H, Lortie A, Vanasse M, Saint-Hilaire JM, Carmant L, Verner A, Lu WY, Wang YT, Rouleau GA (2002) Mutation of the GABRA1 in an Autosomal Dominant Form of Juvenile Myoclonic Epilpesy. Nature Genetics 31:184-189

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rAla294Asp

When this mutant subunit was combined with wild-type b2 and g2L, the GABA sensitivity was significantly reduced.

The effect of Diazepam on the GABA receptors was not affected by this mutation. 100nM of zolpidem and 10mM pentobarbital affected receptors with the a1(A294D) subunit similar to the wild-type.

The average rate of deactivation of the wild-type was 82.5 +/- 3.5ms, but with the a1(A294D) subunit, the deactivation was 8.9 +/- 1.3ms.

Desensitization was significantly slowed by this mutation.

The kinetic properties of the channels openings were compared at GABA concentrations near the EC₅₀ for the wild-type and the EC₅₀ of the mutant. The conductance of the receptors was not affected, but the kinetic properties were affected. The mean open time was significantly reduced.

Fisher JL (2004) A Mutation in the GABAa Receptor a1 subunit linked to human epilepsy affects channel gating properties. NeuroPharmacology 46(5):629-37

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rAla294Glu

The effect on GABA sensitivity was much less than that of A294D. The GABA EC₅₀ was 93.7 +/- 19.2mM, compared to the wild-type of 14.1 +/- 4.3mM

This mutation showed more rapid deactivation than the wild-type, but not as rapid as A294D.

Fisher JL (2004) A Mutation in the GABA_A Receptor a1 subunit linked to human epilepsy affects channel gating properties. NeuroPharmacology 46(5):629-37

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rAla294Lys

This mutation caused a reduction in GABA sensitivity similar to that seen with the negatively charged residues. The EC₅₀ was 183.4mM.

This mutation showed more rapid deactivation than the wild-type, but not as rapid as A294D.

Fisher JL (2004) A Mutation in the GABA_A Receptor a1 subunit linked to human epilepsy affects channel gating properties. NeuroPharmacology 46(5):629-37

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rAla294Asn

This mutation significantly reduced GABA sensitivity with an average EC₅₀ of 55.7 +/- 3.3mM.

This mutation showed more rapid deactivation than the wild-type, similar to A294D.

Fisher JL (2004) A Mutation in the GABA_A Receptor a1 subunit linked to human epilepsy affects channel gating properties. NeuroPharmacology 46(5):629-37

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rAla294Ser

This mutation did not affect GABA EC₅₀, with an average EC₅₀ of 15.3 +/- 4.5mM

This mutation did not affect deactivation.

Fisher JL (2004) A Mutation in the GABA_A Receptor a1 subunit linked to human epilepsy affects channel gating properties. NeuroPharmacology 46(5):629-37

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rAla294Gly

This mutation significantly increased sensitivity to GABA with an EC₅₀ of 2.1 +/- 0.2mM.

This mutation slowed the deactivation rate.

Fisher JL (2004) A Mutation in the GABA_A Receptor a1 subunit linked to human epilepsy affects channel gating properties. NeuroPharmacology 46(5):629-37

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