Synaptic plasticity regulated by stargazin-like gamma-8

描述（由申请人提供）：哺乳动物脑中兴奋性突触的传递主要由作用于AMPA受体和NMDA受体（两类配体门控离子通道）的谷氨酸介导。NMDA受体是突触后致密物（PSD）的稳定成分，而AMPA受体则以受神经元活动严格控制的方式在突触膜上循环和关闭。AMPA受体在突触处的这种受调节的插入和移除提供了改变突触功效和在大脑中存储信息的机制。 我们的初步数据表明，AMPA受体在小脑颗粒细胞的功能性表达需要stargazin，一个大家庭的成员，四个通过跨膜蛋白。而且，我们已经定义了一个跨膜AMPA受体调节蛋白家族（TARPs），其中包括stargazin、gamma 3.，γ-4和γ-8-但不是相关蛋白-介导AMPA受体的表面表达。TARP通过与突触后密度蛋白PSD-95相互作用介导AMPA受体的突触运输。是否stargazin样蛋白控制AMPA受体的营业额和突触可塑性前脑区域，如海马仍然不确定。然而，我们发现其中一种TARP，gamma-8，在海马体中独特地富集，在那里它与AMPA受体相互作用。 我们现在建议，以确定是否γ-8调节活动依赖的AMPA受体贩运的突触可塑性方面的基础。由于磷酸化在活性依赖的AMPA受体运输中起着重要作用，我们将评估海马中γ-8磷酸化的功能作用。我们还将表征功能结构域和蛋白质与γ-8的独特C-末端尾部的相互作用。我们还将采取遗传学方法，并确定γ-8的过表达或靶向破坏如何调节AMPA受体靶向和突触周转。这些研究将为了解突触后发育和功能的机制提供基础。了解控制谷氨酸受体突触靶向的机制将有助于阐明这种可塑性在学习和记忆中的作用。

DESCRIPTION (provided by applicant): Transmission at excitatory synapses in mammalian brain is mediated primarily by glutamate acting on AMPA receptors and NMDA receptors, two classes of ligand gated ion channels. Whereas NMDA receptors are stable components of the postsynaptic density (PSD), AMPA receptors cycle on and off the synaptic membrane in a manner that is tightly controlled by neuronal activity. This regulated insertion and removal of AMPA receptors at the synapse provides a mechanism for altering synaptic efficacy and for storing information in brain. Our preliminary data show that functional expression of AMPA receptors in cerebellar granule cells requires stargazin, a member of a large family of four-pass transmembrane proteins. And, we have defined a family of transmembrane AMPA receptor regulatory proteins (TARPs), which comprise stargazin, gamma3., gamma-4 and gamma-8 - but not related proteins - that mediate surface expression of AMPA receptors. TARPs mediate synaptic trafficking of AMPA receptors by interacting with the postsynaptic density protein, PSD-95. Whether stargazin-like proteins control AMPA receptor turnover and synaptic plasticity in forebrain regions such as hippocampus remains uncertain. However, we found that one of the TARPs, gamma-8, is uniquely enriched in hippocampus, where it interacts with AMPA receptors. We now propose to determine whether gamma-8 regulates the activity-dependent AMPA receptor trafficking that underlies aspects of synaptic plasticity. Because phosphorylation plays a major role in activity-dependent AMPA receptor trafficking, we will assess functional roles for phosphorylation of gamma-8 in hippocampus. We will also characterize functional domains and protein interactions with the unique C-terminal tail of gamma-8. We will also take genetic approaches and determine how overexpression or targeted disruption of gamma-8 modulates AMPA receptor targeting and turnover at synapses. These studies will provide fundamental insight into mechanisms for postsynaptic development and function. Understanding mechanisms that control synaptic targeting of glutamate receptors will help clarify the role that this plasticity plays in learning and memory.