Agonist-dependent endocytosis of γ-aminobutyric acid type A (GABAA) receptors revealed by a γ2(R43Q) epilepsy mutation.
J. Biol. Chem.. 2013-08-09; 288(39): 28254-28265
DOI: 10.1074/jbc.M113.470807
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1. J Biol Chem. 2013 Sep 27;288(39):28254-65. doi: 10.1074/jbc.M113.470807. Epub
2013 Aug 9.
Agonist-dependent endocytosis of γ-aminobutyric acid type A (GABAA) receptors
revealed by a γ2(R43Q) epilepsy mutation.
Chaumont S(1), André C, Perrais D, Boué-Grabot E, Taly A, Garret M.
Author information:
(1)From the Université Bordeaux, Institut de Neurosciences Cognitives et
Intégratives d’Aquitaine (INCIA), UMR 5287, F-33000 Bordeaux, France.
GABA-gated chloride channels (GABAARs) trafficking is involved in the regulation
of fast inhibitory transmission. Here, we took advantage of a γ2(R43Q) subunit
mutation linked to epilepsy in humans that considerably reduces the number of
GABAARs on the cell surface to better understand the trafficking of GABAARs.
Using recombinant expression in cultured rat hippocampal neurons and COS-7 cells,
we showed that receptors containing γ2(R43Q) were addressed to the cell membrane
but underwent clathrin-mediated dynamin-dependent endocytosis. The
γ2(R43Q)-dependent endocytosis was reduced by GABAAR antagonists. These data, in
addition to a new homology model, suggested that a conformational change in the
extracellular domain of γ2(R43Q)-containing GABAARs increased their
internalization. This led us to show that endogenous and recombinant wild-type
GABAAR endocytosis in both cultured neurons and COS-7 cells can be amplified by
their agonists. These findings revealed not only a direct relationship between
endocytosis of GABAARs and a genetic neurological disorder but also that
trafficking of these receptors can be modulated by their agonist.
DOI: 10.1074/jbc.M113.470807
PMCID: PMC3784734
PMID: 23935098 [Indexed for MEDLINE]