Synaptic plasticity regulated by stargazin-like gamma-8

描述(申请人提供)：哺乳动物大脑中兴奋性突触的传递主要通过谷氨酸作用于AMPA受体和NMDA受体，这是两种配体门控离子通道。虽然NMDA受体是突触后密度(PSD)的稳定成分，但AMPA受体以一种严格受神经元活动控制的方式在突触膜上和突触外循环。这种受调控的AMPA受体在突触上的插入和移除为改变突触效率和在大脑中存储信息提供了一种机制。 我们的初步数据表明，AMPA受体在小脑颗粒细胞中的功能表达需要Stargazin，它是一个四通道跨膜蛋白大家族的成员。并且，我们定义了一个跨膜AMPA受体调节蛋白家族(TARP)，它包括Stargazin、Gamma3、Gamma-4和Gamma-8，但不包括相关蛋白，它们介导AMPA受体的表面表达。Tarps通过与突触后密度蛋白PSD-95相互作用来介导AMPA受体的突触运输。Stargazin样蛋白是否控制AMPA受体的更新和前脑区域(如海马区)的突触可塑性仍不确定。然而，我们发现其中一种Tarp，伽马-8，在海马体中特别丰富，在那里它与AMPA受体相互作用。 我们现在建议确定伽马-8是否调节作为突触可塑性基础的活性依赖的AMPA受体运输。由于磷酸化在活性依赖的AMPA受体运输中起主要作用，我们将评估在海马区伽马-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伽马-8独特的C-末端尾巴的相互作用。我们还将采用遗传学方法，并确定伽马-8的过度表达或靶向破坏如何调节AMPA受体靶向和突触的周转。这些研究将为突触后发育和功能的机制提供基本的见解。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所起的作用。

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.