Cingolani Lorenzo A, Thalhammer Agnes, Yu Lily M Y, Catalano Myriam, Ramos Timothy, Colicos Michael A, Goda Yukiko
MRC Laboratory for Molecular Cell Biology and Cell Biology Unit, University College London, Gower Street, London WC1E 6BT, UK.
Neuron. 2008 Jun 12;58(5):749-62. doi: 10.1016/j.neuron.2008.04.011.
At synapses, cell adhesion molecules (CAMs) provide the molecular framework for coordinating signaling events across the synaptic cleft. Among synaptic CAMs, the integrins, receptors for extracellular matrix proteins and counterreceptors on adjacent cells, are implicated in synapse maturation and plasticity and memory formation. However, little is known about the molecular mechanisms of integrin action at central synapses. Here, we report that postsynaptic beta3 integrins control synaptic strength by regulating AMPA receptors (AMPARs) in a subunit-specific manner. Pharmacological perturbation targeting beta3 integrins promotes endocytosis of GluR2-containing AMPARs via Rap1 signaling, and expression of beta3 integrins produces robust changes in the abundance and composition of synaptic AMPARs without affecting dendritic spine structure. Importantly, homeostatic synaptic scaling induced by activity deprivation elevates surface expression of beta3 integrins, and in turn, beta3 integrins are required for synaptic scaling. Our findings demonstrate a key role for integrins in the feedback regulation of excitatory synaptic strength.
在突触处，细胞粘附分子（CAMs）为协调跨突触间隙的信号传导事件提供分子框架。在突触CAMs中，整合素作为细胞外基质蛋白的受体以及相邻细胞上的反受体，与突触成熟、可塑性和记忆形成有关。然而，关于整合素在中枢突触处作用的分子机制知之甚少。在此，我们报告突触后β3整合素通过以亚基特异性方式调节AMPA受体（AMPARs）来控制突触强度。靶向β3整合素的药理学扰动通过Rap1信号传导促进含GluR2的AMPARs的内吞作用，并且β3整合素的表达在不影响树突棘结构的情况下使突触AMPARs的丰度和组成产生显著变化。重要的是，由活动剥夺诱导的稳态突触缩放会提高β3整合素的表面表达，反过来，突触缩放需要β3整合素。我们的研究结果证明了整合素在兴奋性突触强度的反馈调节中的关键作用。
