α/β-Hydrolase domain-containing 6 (ABHD6) negatively regulates the surface delivery and synaptic function of AMPA receptors.
In the brain, AMPA-type glutamate receptors are major postsynaptic receptors at excitatory synapses that mediate fast neurotransmission and synaptic plasticity. α/β-Hydrolase domain-containing 6 (ABHD6), a monoacylglycerol lipase, was previously found to be a component of AMPA receptor macromolecular complexes, but its physiological significance in the function of AMPA receptors (AMPARs) has remained unclear. The present study shows that overexpression of ABHD6 in neurons drastically reduced excitatory neurotransmission mediated by AMPA but not by NMDA receptors at excitatory synapses. Inactivation of ABHD6 expression in neurons by either CRISPR/Cas9 or shRNA knockdown methods significantly increased excitatory neurotransmission at excitatory synapses. Interestingly, overexpression of ABHD6 reduced glutamate-induced currents and the surface expression of GluA1 in HEK293T cells expressing GluA1 and stargazin, suggesting a direct functional interaction between these two proteins. The C-terminal tail of GluA1 was required for the binding between of ABHD6 and GluA1. Mutagenesis analysis revealed a GFCLIPQ sequence in the GluA1 C terminus that was essential for the inhibitory effect of ABHD6. The hydrolase activity of ABHD6 was not required for the effects of ABHD6 on AMPAR function in either neurons or transfected HEK293T cells. Thus, these findings reveal a novel and unexpected mechanism governing AMPAR trafficking at synapses through ABHD6.
State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China;
Mengping
M
Wei
State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China;
Jian
J
Zhang
State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China;
Moye
M
Jia
State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China;
Chaojuan
C
Yang
State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China;
Yunlong
Y
Pan
State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China;
Shuaiqi
S
Li
State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China;
Yiwen
Y
Luo
State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China;
Junyuan
J
Zheng
State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China;
Jianguo
J
Ji
State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China;
Jianguo
J
Chen
Institute of Molecular Medicine, Peking University, Beijing 100871, China;
Xinli
X
Hu
Institute of Molecular Medicine, Peking University, Beijing 100871, China;
Jingwei
J
Xiong
MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, Jiangsu 210067, China;
Yun
Y
Shi
State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China; Beijing Institute of Collaborative Innovation, Beijing 100871, China ch.zhang@pku.edu.cn.
Chen
C
Zhang
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D006801:Humans; D051379:Mice; D008994:Monoacylglycerol Lipases / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D000072417:Protein Domains / Q000502:physiology; D018091:Receptors, AMPA / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
D018091:Receptors, AMPA; C527261:ABHD6 protein, mouse; D008994:Monoacylglycerol Lipases
ABHD6; AMPA receptor; receptor trafficking; synapses