GODZ-mediated palmitoylation of GABAA receptors is required for normal assembly and function of GABAergic inhibitory synapses
GODZ-mediated palmitoylation of GABAA receptors is required for normal assembly and function of GABAergic inhibitory synapses
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DOI：
10.1523/jneurosci.4214-06.2006
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发表时间：
2006-12-06
影响因子：
5.3
通讯作者：
Luscher, Bernhard
中科院分区：
文献类型：
--
作者：
Fang, Cheng;Deng, Lunbin;Luscher, Bernhard
高尔基体特异性DHHC（Asp-His-His-Cys）锌指蛋白（GODZ）是DHHC家族棕榈酰酰基转移酶，其涉及棕榈酰化和调节在抑制性或兴奋性突触处起作用的多种底物的运输。特别感兴趣的是GABAA受体的γ 2亚基，其是将这些受体靶向抑制性突触所需的。在这里，我们报告说，GODZ，并在较小程度上，其关闭paracentralsertoli细胞基因与锌指结构域-β（SERZ-β）的DHHC家族的酶，能够棕榈酰化的γ 2亚基在异源细胞的主要成员。在人胚肾293 T（HEK 293 T）细胞中的酵母双杂交和共定位试验表明，GODZ和SERZ-β与γ 2亚基显示出不可区分的棕榈酰化依赖性相互作用。在HEK 293 T细胞中共表达后，它们形成同多聚体和异多聚体，如通过免疫共沉淀和体内交联实验所示。在用显性阴性GODZ（GODZ（C157 S））或基于质粒的GODZ特异性RNAi转染的神经元中的分析表明，GODZ是GABA（A）受体在突触处的正常积累、正常的全细胞和突触GABA能抑制功能以及间接地GABA能神经支配所必需的。出乎意料的是，GODZ被发现对正常的突触后AMPA受体介导的突触能传递是无效的。我们的结论是，GODZ介导的GABAA受体和可能的其他底物的棕榈酰化选择性地有助于GABA能抑制性突触的形成和正常功能。
Golgi-specific DHHC (Asp-His-His-Cys) zinc finger protein (GODZ) is a DHHC family palmitoyl acyltransferase that is implicated in palmitoylation and regulated trafficking of diverse substrates that function either at inhibitory or excitatory synapses. Of particular interest is the gamma 2 subunit of GABAA receptors, which is required for targeting these receptors to inhibitory synapses. Here, we report that GODZ and, to a lesser extent, its close paralog sertoli cell gene with a zinc finger domain-beta (SERZ-beta) are the main members of the DHHC family of enzymes that are able to palmitoylate the gamma 2 subunit in heterologous cells. Yeast two-hybrid and colocalization assays in human embryonic kidney 293T (HEK293T) cells indicate that GODZ and SERZ-beta show indistinguishable palmitoylation-dependent interaction with the gamma 2 subunit. After coexpression in HEK293T cells, they form homomultimers and heteromultimers, as shown by coimmunoprecipitation and in vivo cross-linking experiments. Analyses in neurons transfected with dominant-negative GODZ (GODZ(C157S)) or plasmid-based GODZ-specific RNAi indicate that GODZ is required for normal accumulation of GABA(A) receptors at synapses, for normal whole-cell and synaptic GABAergic inhibitory function and, indirectly, for GABAergic innervation. Unexpectedly, GODZ was found to be dispensable for normal postsynaptic AMPA receptor-mediated glutamatergic transmission. We conclude that GODZ-mediated palmitoylation of GABAA receptors and possibly other substrates contributes selectively to the formation and normal function of GABAergic inhibitory synapses.