Epac2-mediated dendritic spine remodeling: implications for disease.
Epac2-mediated dendritic spine remodeling: implications for disease.
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EPAC2介导的树突状脊柱重塑：对疾病的影响。
DOI：
10.1016/j.mcn.2010.11.008
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发表时间：
2011-02
影响因子：
3.5
通讯作者：
Srivastava, Deepak P.
中科院分区：
文献类型：
--
作者：
Penzes, Peter;Woolfrey, Kevin M.;Srivastava, Deepak P.
在哺乳动物的前脑中，大多数突触发生在称为树突棘的小树突突起上。树突棘是高度可塑的，并且可以响应于许多刺激而迅速改变形态。树突棘的这种动态重塑被认为对信息处理、记忆和认知至关重要。相反，多项研究表明，自闭症谱系障碍（ASD）等神经病理学与树突棘形态学的改变和神经回路的错误连接有关。一个令人信服的假设是，异常树突棘重塑是这种错误布线的关键因素。正在进行的研究已经确定了一些机制，是至关重要的树突棘重塑的控制。在这些机制中，鸟嘌呤核苷酸交换因子（GEF）调节小GTdR信号传导正在成为整合生理信号控制树突棘重塑的关键机制。此外，与树突棘重塑的调节相关的多种蛋白质也与多种神经病理学有关，包括ASD。Epac 2是小GTdR β的GEF，最近被描述为定位于树突棘的新型cAMP（但不依赖于PKA）靶点。通过多巴胺D1/5受体，通过这种蛋白质响应药理学刺激或cAMP积累的信号传导导致Rap激活，以树突棘收缩的形式促进结构不稳定，以及由于去除含GluR 2/3的AMPA受体而导致的功能抑制。此外，Epac 2与ASD相关蛋白形成大分子复合物，足以调节Epac 2的定位和功能。此外，与ASD表型相关的EPAC 2基因的罕见非同义变体改变蛋白质功能、突触蛋白分布和棘形态。我们在这里回顾Epac 2在正常条件下树突棘重塑中的作用，这些作用的机制，以及这些疾病相关变体对我们理解ASD病理生理的影响。
In the mammalian forebrain, most glutamatergic excitatory synapses occur on small dendritic protrusions called dendritic spines. Dendritic spines are highly plastic and can rapidly change morphology in response to numerous stimuli. This dynamic remodeling of dendritic spines is thought to be critical for information processing, memory and cognition. Conversely, multiple studies have revealed that neuropathologies such as autism spectrum disorders (ASDs) are linked with alterations in dendritic spine morphologies and miswiring of neural circuitry. One compelling hypothesis is that abnormal dendritic spine remodeling is a key contributing factor for this miswiring. Ongoing research has identified a number of mechanisms that are critical for the control of dendritic spine remodeling. Among these mechanisms, regulation of small GTPase signaling by guanine-nucleotide exchange factors (GEFs) is emerging as a critical mechanism for integrating physiological signals in the control of dendritic spine remodeling. Furthermore, multiple proteins associated with regulation of dendritic spine remodeling have also been implicated with multiple neuropathologies, including ASDs. Epac2, a GEF for the small GTPase Rap, has recently been described as a novel cAMP(yet PKA-independent) target localized to dendritic spines. Signaling via this protein in response to pharmacological stimulation or cAMP accumulation, via the dopamine D1/5 receptor, results in Rap activation, promotes structural destabilization, in the form of dendritic spine shrinkage, and functional depression due to removal of GluR2/3-containing AMPA receptors. In addition, Epac2 forms macromolecular complexes with ASD-associated proteins, which are sufficient to regulate Epac2 localization and function. Furthermore, rare nonsynonymous variants of the EPAC2 gene associated with the ASD phenotype alter protein function, synaptic protein distribution, and spine morphology. We review here the role of Epac2 in the remodeling of dendritic spines under normal conditions, the mechanisms that underlie these effects, and the implications these disease-associated variants have on our understanding of the pathophysiology of ASD.
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