School of Biochemistry, Centre for Synaptic Plasticity, Medical Sciences Building and Dorothy Hodgkin Building, University of Bristol, University Walk, Bristol BS8 1TD, UK.
Neuron. 2013 Jul 24;79(2):293-307. doi: 10.1016/j.neuron.2013.05.003.
Inhibition of Arp2/3-mediated actin polymerization by PICK1 is a central mechanism to AMPA receptor (AMPAR) internalization and long-term depression (LTD), although the signaling pathways that modulate this process in response to NMDA receptor (NMDAR) activation are unknown. Here, we define a function for the GTPase Arf1 in this process. We show that Arf1-GTP binds PICK1 to limit PICK1-mediated inhibition of Arp2/3 activity. Expression of mutant Arf1 that does not bind PICK1 leads to reduced surface levels of GluA2-containing AMPARs and smaller spines in hippocampal neurons, which occludes subsequent NMDA-induced AMPAR internalization and spine shrinkage. In organotypic slices, NMDAR-dependent LTD of AMPAR excitatory postsynaptic currents is abolished in neurons expressing mutant Arf1. Furthermore, NMDAR stimulation downregulates Arf1 activation and binding to PICK1 via the Arf-GAP GIT1. This study defines Arf1 as a critical regulator of actin dynamics and synaptic function via modulation of PICK1.
PICK1 抑制 Arp2/3 介导的肌动蛋白聚合是 AMPA 受体 (AMPAR) 内化和长时程抑郁 (LTD) 的核心机制，尽管调节该过程的信号通路尚不清楚。在这里，我们定义了 GTPase Arf1 在这个过程中的一个功能。我们表明，Arf1-GTP 与 PICK1 结合，限制 PICK1 对 Arp2/3 活性的抑制。表达不与 PICK1 结合的突变型 Arf1 会导致海马神经元中含有 GluA2 的 AMPAR 表面水平降低和棘突变小，从而阻断随后的 NMDA 诱导的 AMPAR 内化和棘突收缩。在器官型切片中，表达突变型 Arf1 的神经元中 NMDA 依赖性 AMPAR 兴奋性突触后电流的 LTD 被消除。此外，NMDAR 刺激通过 Arf-GAP GIT1 下调 Arf1 的激活和与 PICK1 的结合。这项研究通过调节 PICK1，将 Arf1 定义为肌动蛋白动态和突触功能的关键调节剂。
