RT Journal Article SR Electronic T1 δ Subunit Susceptibility Variants E177A and R220H Associated with Complex Epilepsy Alter Channel Gating and Surface Expression of α4β2δ GABAA Receptors JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 1499 OP 1506 DO 10.1523/JNEUROSCI.2913-05.2006 VO 26 IS 5 A1 Hua-Jun Feng A1 Jing-Qiong Kang A1 Luyan Song A1 Leanne Dibbens A1 John Mulley A1 Robert L. Macdonald YR 2006 UL http://www.jneurosci.org/content/26/5/1499.abstract AB Most human idiopathic generalized epilepsies (IGEs) are polygenic, but virtually nothing is known of the molecular basis for any of the complex epilepsies. Recently, two GABAA receptor δ subunit variants (E177A, R220H) were proposed as susceptibility alleles for generalized epilepsy with febrile seizures plus and juvenile myoclonic epilepsy. In human embryonic kidney 293T cells, recombinant hα1β2δ(E177A) and hα1β2δ(R220H) receptor currents were reduced, but the basis for the current reduction was not determined. We examined the mechanistic basis for the current reduction produced by these variants using the hα4β2δ receptor, an isoform more physiologically relevant and linked to epileptogenesis, by characterizing the effects of these variants on receptor cell surface expression and single-channel gating properties. Expression of variant α4β2δ(R220H) receptors resulted in a decrease in surface receptor proteins, and a smaller, but significant, reduction was observed for variant α4β2δ(E177A) receptors. For both variants, no significant alterations of surface expression were observed for mixed population of wild-type and variant receptors. The mean open durations of α4β2δ(E177A) and α4β2δ(R220H) receptor single-channel currents were both significantly decreased compared to wild-type receptors. These data suggest that both δ(E177A) and δ(R220H) variants may result in disinhibition in IGEs by similar cellular and molecular mechanisms, and in heterozygously affected individuals, a reduction in channel open duration of δ subunit-containing GABAA receptors may be the major contributor to the epilepsy phenotypes.