GABAA receptor trafficking is regulated by protein kinase C(epsilon) and the N-ethylmaleimide-sensitive factor.
Disturbances in GABA(A) receptor trafficking contribute to several neurological and psychiatric disorders by altering inhibitory neurotransmission. Identifying mechanisms that regulate GABA(A) receptor trafficking could lead to better understanding of disease pathogenesis and treatment. Here, we show that protein kinase Cε (PKCε) regulates the N-ethylmaleimide-sensitive factor (NSF), an ATPase critical for membrane fusion events, and thereby promotes the trafficking of GABA(A) receptors. Activation of PKCε decreased cell surface expression of GABA(A) receptors and attenuated GABA(A) currents. Activated PKCε associated with NSF, phosphorylated NSF at serine 460 and threonine 461, and increased NSF ATPase activity, which was required for GABA(A) receptor downregulation. These findings identify new roles for NSF and PKCε in regulating synaptic inhibition through downregulation of GABA(A) receptors. Reducing NSF activity by inhibiting PKCε could help restore synaptic inhibition in disease states in which it is impaired.
Ernest Gallo Clinic and Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94688, USA.
Wen-Hai
WH
Chou
Dan
D
Wang
Thomas
T
McMahon
Zhan-Heng
ZH
Qi
Maengseok
M
Song
Chao
C
Zhang
Kevan M
KM
Shokat
Robert O
RO
Messing
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D019921:Biotinylation; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004594:Electrophysiology; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D052066:N-Ethylmaleimide-Sensitive Proteins / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*
D011956:Receptors, Cell Surface; D011963:Receptors, GABA-A; D051744:Protein Kinase C-epsilon; D000251:Adenosine Triphosphatases; D052066:N-Ethylmaleimide-Sensitive Proteins