Altered kinetics and benzodiazepine sensitivity of a GABAA receptor subunit mutation [g2(R43Q)] found in human epilepsy

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dc.contributor.authorBowser, D.
dc.contributor.authorWagner, D.
dc.contributor.authorCzajkowski, C.
dc.contributor.authorCromer, B.
dc.contributor.authorParker, M.
dc.contributor.authorWallace, R.
dc.contributor.authorHarkin, L.
dc.contributor.authorMulley, J.
dc.contributor.authorMarini, C.
dc.contributor.authorBerkovic, S.
dc.contributor.authorWilliams, D.
dc.contributor.authorJones, M.
dc.contributor.authorPetrou, S.
dc.date.issued2002
dc.description.abstractThe gamma-aminobutyric acid type A (GABA(A)) receptor mediates fast inhibitory synaptic transmission in the CNS. Dysfunction of the GABA(A) receptor would be expected to cause neuronal hyperexcitability, a phenomenon linked with epileptogenesis. We have investigated the functional consequences of an arginine-to-glutamine mutation at position 43 within the GABA(A) gamma(2)-subunit found in a family with childhood absence epilepsy and febrile seizures. Rapid-application experiments performed on receptors expressed in HEK-293 cells demonstrated that the mutation slows GABA(A) receptor deactivation and increases the rate of desensitization, resulting in an accumulation of desensitized receptors during repeated, short applications. In Xenopus laevis oocytes, two-electrode voltage-clamp analysis of steady-state currents obtained from alpha(1)beta(2)gamma(2) or alpha(1)beta(2)gamma(2)(R43Q) receptors did not reveal any differences in GABA sensitivity. However, differences in the benzodiazepine pharmacology of mutant receptors were apparent. Mutant receptors expressed in oocytes displayed reduced sensitivity to diazepam and flunitrazepam but not the imidazopyridine zolpidem. These results provide evidence of impaired GABA(A) receptor function that could decrease the efficacy of transmission at inhibitory synapses, possibly generating a hyperexcitable neuronal state in thalamocortical networks of epileptic patients possessing the mutant subunit.
dc.description.statementofresponsibilityDavid N. Bowser, David A. Wagner, Cynthia Czajkowski, Brett A. Cromer, Michael W. Parker, Robyn H. Wallace, Louise A. Harkin, John C. Mulley, Carla Marini, Samuel F. Berkovic, David A. Williams, Mathew V. Jones and Steven Petrou
dc.identifier.citationNeuroscience, 2002; 99(23):15170-15175
dc.identifier.doi10.1073/pnas.212320199
dc.identifier.issn0306-4522
dc.identifier.issn1091-6490
dc.identifier.urihttp://hdl.handle.net/2440/28203
dc.language.isoen
dc.publisherPergamon-Elsevier Science Ltd
dc.source.urihttps://doi.org/10.1073/pnas.212320199
dc.subjectrapid agonist application
dc.subjecttwo-electrode voltage clamp
dc.subjectXenopus oocytes
dc.titleAltered kinetics and benzodiazepine sensitivity of a GABAA receptor subunit mutation [g2(R43Q)] found in human epilepsy
dc.typeJournal article
pubs.publication-statusPublished

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