Neurobiology Section, Division of Biology, University of California, San Diego, La Jolla, CA 92093, USA.
Neuron. 2009 Dec 24;64(6):799-806. doi: 10.1016/j.neuron.2009.12.019.
We identify the leucine-rich repeat transmembrane protein LRRTM2 as a key regulator of excitatory synapse development and function. LRRTM2 localizes to excitatory synapses in transfected hippocampal neurons, and shRNA-mediated knockdown of LRRTM2 leads to a decrease in excitatory synapses without affecting inhibitory synapses. LRRTM2 interacts with PSD-95 and regulates surface expression of AMPA receptors, and lentivirus-mediated knockdown of LRRTM2 in vivo decreases the strength of evoked excitatory synaptic currents. Structure-function studies indicate that LRRTM2 induces presynaptic differentiation via the extracellular LRR domain. We identify Neurexin1 as a receptor for LRRTM2 based on affinity chromatography. LRRTM2 binds to both Neurexin 1alpha and Neurexin 1beta, and shRNA-mediated knockdown of Neurexin1 abrogates LRRTM2-induced presynaptic differentiation. These observations indicate that an LRRTM2-Neurexin1 interaction plays a critical role in regulating excitatory synapse development.
我们鉴定出富含亮氨酸重复跨膜蛋白 LRRTM2 是调节兴奋性突触发育和功能的关键调控因子。LRRTM2 在转染的海马神经元中定位于兴奋性突触，并且 shRNA 介导的 LRRTM2 敲低导致兴奋性突触减少而不影响抑制性突触。LRRTM2 与 PSD-95 相互作用并调节 AMPA 受体的表面表达，并且体内慢病毒介导的 LRRTM2 敲低降低了诱发的兴奋性突触电流的强度。结构功能研究表明，LRRTM2 通过细胞外 LRR 结构域诱导突触前分化。我们基于亲和层析鉴定出 Neurexin1 是 LRRTM2 的受体。LRRTM2 与 Neurexin 1alpha 和 Neurexin 1beta 结合，并且 shRNA 介导的 Neurexin1 敲低消除了 LRRTM2 诱导的突触前分化。这些观察结果表明，LRRTM2-Neurexin1 相互作用在调节兴奋性突触发育中起着关键作用。
