Protein Trafficking Regulating the Formation of GABAergic Synapses

项目摘要 神经抑制？-氨基丁酸（GABA）对正常的大脑功能至关重要， GABA能传递的缺陷与广泛的破坏性神经和精神疾病相关， 包括癫痫、焦虑、情绪障碍、精神发育迟滞和许多其他的疾病。赤字 GABA能传递通常与表达、细胞分布或功能缺陷有关。 GABA-A受体的特性。在这里，我们专注于棕榈酰化作为一个至关重要的机制， 控制GABA-A受体和突触细胞粘附分子神经连接素的运输，两者都是 对GABA能抑制性突触传递至关重要。初步实验表明， GABA-A受体的γ 2亚基和神经配蛋白2（NL 2）在体外被相同的选择性棕榈酰化 结构上相关的棕榈酰转移酶，GODZ和SERZ-β（也称为zDHHC 3和7）。棕榈酰 突触后神经元中的这些酶有助于GABA-A受体的正常运输， GABA能神经支配和GABA能突触的正常功能。此外，NL 2在 突触需要含有GABA-A受体的突触后γ 2亚单位。所有这些 初步研究结果使我们提出了核心假设，即GODZ/SERZ-<$-介导的 NL 2和GABA-A受体之间的棕榈酰化和功能协同性在 GABA能抑制性突触的形成和突触后分化。为了进一步验证这一点 假设我们将i）测试GODD/SERZ-<$在GABA-A棕榈酰化和运输中的功能 受体，ii）测试GODD/SERZ-<$在NL 2的棕榈酰化和运输中的功能，以及iii）分析 之间的协同性？含GABA-A受体2亚单位和NL 2在GABA能神经元形成中的作用 突触总之，这些实验将提供一个彻底的了解机制，有助于 GABAA受体在GABA能终末的忠实并置，从而有助于 GABA能抑制性突触的组装和分化。

Project Summary Neural inhibition by ?-aminobutyric acid (GABA) is vitally important for normal brain function as is evident from deficits in GABAergic transmission associated with a wide range of devastating neurological and psychiatric disorders including epilepsy, anxiety, mood disorders, mental retardation, and many others. Deficits in GABAergic transmission are commonly associated with deficits in expression, cellular distribution, or functional properties of GABA-A receptors. Here we focus on palmitoylation as a critically important mechanism that controls the trafficking of GABA-A receptors and the synaptic cell adhesion molecule neuroligin, which both are critically important for GABAergic inhibitory synaptic transmission. Our preliminary experiments show that the gamma2 subunit of GABA-A receptors and neuroligin 2 (NL2) are in vitro palmitoylated selectively by the same struturally related palmitoyltransferases, GODZ and SERZ-beta (also known as zDHHC3 and 7). Palmitoylation by these enzymes in postsynaptic neurons contributes to normal trafficking of GABA-A receptors, normal GABAergic innervation and normal function of GABAergic synapses. Moreover, accumulation of NL2 at synapses requires postsynaptic gamma2 subunit containing GABA-A receptors. Together, these preliminary findings lead us to propose the central hypothesis that GODZ/SERZ-¿-mediated palmitoylation and functional cooperativity between NL2 and GABA-A receptors play important roles in formation and postsynaptic differentiation of GABAergic inhibitory synapses. To further test this hypothesis we will i) test the function of GODD/SERZ-¿ in palmitoylation and trafficking of GABA-A receptors, ii) test the function of GODD/SERZ-¿ in palmitoylation and trafficking of NL2, and iii) analyze cooperativity between ?2 subunit-containing GABA-A receptors and NL2 in the formation of GABAergic synapses. Together these experiments will provide a thorough understanding of a mechanism that contributes to faithful apposition of GABAA receptors across form GABAergic terminals and thereby contributes to assembly and differentiation of GABAergic inhibitory synapses.