Agonist-dependent Endocytosis of gamma-Aminobutyric Acid Type A (GABA(A)) Receptors Revealed by a gamma 2(R43Q) Epilepsy Mutation

作者：Chaumont Severine; Andre Caroline; Perrais David; Boue Grabot Eric; Taly Antoine; Garret Maurice^*

来源：Journal of Biological Chemistry, 2013, 288(39): 28254-28265.

DOI：10.1074/jbc.M113.470807

GABA-gated chloride channels (GABA(A)Rs) trafficking is involved in the regulation of fast inhibitory transmission. Here, we took advantage of a gamma 2(R43Q) subunit mutation linked to epilepsy in humans that considerably reduces the number of GABA(A)Rs on the cell surface to better understand the trafficking of GABA(A)Rs. Using recombinant expression in cultured rat hippocampal neurons and COS-7 cells, we showed that receptors containing gamma 2(R43Q) were addressed to the cell membrane but underwent clathrin-mediated dynamin-dependent endocytosis. The gamma 2(R43Q)-dependent endocytosis was reduced by GABA(A)R antagonists. These data, in addition to a new homology model, suggested that a conformational change in the extracellular domain of gamma 2(R43Q)-containing GABA(A)Rs increased their internalization. This led us to show that endogenous and recombinant wild-type GABA(A)R 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 GABA(A)Rs and a genetic neurological disorder but also that trafficking of these receptors can be modulated by their agonist.

• 出版日期2013-9-27