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Alpha/beta-hydrolase domain-containing 6(ABHD6) negatively regulates the surface delivery and synaptic function of AMPA receptors

Mengping Wei  Jian Zhang  Moye Jia  Chaojuan Yang  Yunlong Pan  Shuaiqi Li  Yiwen Luo  Junyuan Zheng  Jianguo Ji  Jianguo Chen  Xinli Hu  Jingwei Xiong  Yun Shi  Chen Zhang  
【摘要】:In the brain, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid(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 showed that overexpression of ABHD6 in neurons drastically reduced excitatory neurotransmission mediated by AMPA but not by N-methyl-D-aspartate receptors(NMDARs) at excitatory synapses. Inactivation of ABHD6 expression in neurons by either CRISPR/Cas9 or sh RNA knockdown methods significantly increased excitatory neurotransmission at excitatory synapses. Interestingly, overexpression of ABHD6 reduced glutamate-induced currents and the surface expression of Glu A1 in HEK293 T cells expressing Glu A1 and stargazin, suggesting a direct functional interaction between these two proteins. The C-terminal tail of Glu A1 was required for the binding between of ABHD6 and Glu A1. Mutagenesis analysis revealed a GFCLIPQ sequence in the GluA1C-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 HEK293 T cells. Thus, these findings reveal a novel and expected mechanism governing AMPAR trafficking at synapses through ABHD6.

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