An asymmetric contribution to gamma-aminobutyric type A receptor function of a conserved lysine within TM2-3 of alpha1, beta2, and gamma2 subunits.

The Journal of Biological Chemistry
T G HalesChristopher N Connolly

Abstract

Mutations that impair the expression and/or function of gamma-aminobutyric acid type A (GABAA) receptors can lead to epilepsy. The familial epilepsy gamma2(K289M) mutation affects a basic residue conserved in the TM2-3 linker of most GABAA subunits. We investigated the effect on expression and function of the Lys --> Met mutation in mouse alpha1(K278M), beta2(K274M), and gamma2(K289M) subunits. Compared with cells expressing wild-type and alpha1beta2gamma2(K289M) receptors, cells expressing alpha1(K278M)beta2gamma2 and alpha1beta2(K274M)gamma2 receptors exhibited reduced agonist-evoked current density and reduced GABA potency, with no change in single channel conductance. The low current density of alpha1beta2(K274M)gamma2 receptors coincided with reduced surface expression. By contrast the surface expression of alpha1(K278M)beta2gamma2 receptors was similar to wild-type and alpha1beta2gamma2(K289M) receptors suggesting that the alpha1(K278M) impairs function. In keeping with this interpretation GABA-activated channels mediated by alpha1(K278M)beta2gamma2 receptors had brief open times. To a lesser extent gamma2(K289M) also reduced mean open time, whereas beta2(K274M) had no effect. We used propofol as an alternative GABAA rece...Continue Reading

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Citations

Mar 31, 2010·Pflügers Archiv : European journal of physiology·Aristea S Galanopoulou
Jul 29, 2008·The Journal of Biological Chemistry·Daniel K CrawfordRonald L Alkana
Mar 5, 2010·The Journal of Pharmacology and Experimental Therapeutics·Paula L Feinberg-Zadek, Paul A Davies
Jan 22, 2008·Molecular and Cellular Neurosciences·Karen A BollanChristopher N Connolly
Apr 18, 2018·Expert Reviews in Molecular Medicine·Hao DengZhi Song
Oct 3, 2017·Nature Structural & Molecular Biology·Duncan LavertyTrevor G Smart
May 20, 2016·The Journal of Physiology·Daniel T Baptista-HonTim G Hales
Dec 14, 2018·The Journal of Biological Chemistry·Carla Gottschald ChiodiTim G Hales
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Oct 21, 2006·Biochemical Society Transactions·S MizielinskaC N Connolly
Dec 17, 2016·The Journal of Physiology·Daniel T Baptista-HonTim G Hales
Sep 30, 2018·Nature Communications·Qiang ChenPei Tang

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