Ethanol alters trafficking and functional N-methyl-D-aspartate receptor NR2 subunit ratio via H-Ras.
The N-methyl-D-aspartate receptor (NMDAR) plays a critical role in synaptic plasticity and is one of the main targets for alcohol (ethanol) in the brain. Trafficking of the NMDAR is emerging as a key regulatory mechanism that underlies channel activity and synaptic plasticity. Here we show that exposure of hippocampal neurons to ethanol increases the internalization of the NR2A but not NR2B subunit of the NMDAR via the endocytic pathway. We further observed that ethanol exposure results in NR2A endocytosis through the activation of H-Ras and the inhibition of the tyrosine kinase Src. Importantly, ethanol treatment alters functional subunit composition from NR2A/NR2B- to mainly NR2B-containing NMDARs. Our results suggest that addictive drugs such as ethanol alter NMDAR trafficking and subunit composition. This may be an important mechanism by which ethanol exerts its effects on NMDARs to produce alcohol-induced aberrant plasticity.
Suvarna
Neesha
N
Ernest Gallo Research Center, Emeryville, California 94608, USA.
Borgland
Stephanie L
SL
Wang
Jun
J
Phamluong
Khanhky
K
Auberson
Yves P
YP
Bonci
Antonello
A
Ron
Dorit
D
D033962:Adaptor Protein Complex 2 / Q000378:metabolism; D000818:Animals; D000431:Ethanol / Q000494:pharmacology*; D007739:L Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000378:metabolism / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism* / Q000502:physiology; D018631:ras Proteins / Q000502:physiology*
D033962:Adaptor Protein Complex 2; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; D018631:ras Proteins