Kalinowska Magdalena, Chávez Andrés E, Lutzu Stefano, Castillo Pablo E, Bukauskas Feliksas F, Francesconi Anna
From the Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461.
From the Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461
J Biol Chem. 2015 Jun 26;290(26):15909-20. doi: 10.1074/jbc.M115.640136. Epub 2015 May 5.
Dendritic spines are dynamic, actin-rich protrusions in neurons that undergo remodeling during neuronal development and activity-dependent plasticity within the central nervous system. Although group 1 metabotropic glutamate receptors (mGluRs) are critical for spine remodeling under physiopathological conditions, the molecular components linking receptor activity to structural plasticity remain unknown. Here we identify a Ca(2+)-sensitive actin-binding protein, α-actinin-4, as a novel group 1 mGluR-interacting partner that orchestrates spine dynamics and morphogenesis in primary neurons. Functional silencing of α-actinin-4 abolished spine elongation and turnover stimulated by group 1 mGluRs despite intact surface receptor expression and downstream ERK1/2 signaling. This function of α-actinin-4 in spine dynamics was underscored by gain-of-function phenotypes in untreated neurons. Here α-actinin-4 induced spine head enlargement, a morphological change requiring the C-terminal domain of α-actinin-4 that binds to CaMKII, an interaction we showed to be regulated by group 1 mGluR activation. Our data provide mechanistic insights into spine remodeling by metabotropic signaling and identify α-actinin-4 as a critical effector of structural plasticity within neurons.
树突棘是神经元中动态的、富含肌动蛋白的突起，在中枢神经系统的神经元发育和依赖活动的可塑性过程中会发生重塑。尽管1型代谢型谷氨酸受体（mGluRs）在生理病理条件下对棘突重塑至关重要，但将受体活性与结构可塑性联系起来的分子成分仍不清楚。在这里，我们鉴定出一种钙敏感的肌动蛋白结合蛋白α-辅肌动蛋白-4，它是一种新型的与1型mGluR相互作用的伴侣，可协调原代神经元中的棘突动态和形态发生。尽管表面受体表达和下游ERK1/2信号完整，但α-辅肌动蛋白-4的功能沉默消除了1型mGluRs刺激的棘突伸长和周转。α-辅肌动蛋白-4在棘突动态中的这种功能在未处理的神经元的功能获得表型中得到了强调。在这里，α-辅肌动蛋白-4诱导棘突头部增大，这种形态变化需要α-辅肌动蛋白-4与CaMKII结合的C末端结构域，我们发现这种相互作用受1型mGluR激活的调节。我们的数据为代谢型信号传导介导的棘突重塑提供了机制性见解，并确定α-辅肌动蛋白-4是神经元内结构可塑性的关键效应因子。
