Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA; Graduate Program in Neuroscience, University of Washington, Seattle, WA 98195, USA.
Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA; Graduate Program in Molecular and Cellular Biology, University of Washington, Seattle, WA 98195, USA.
Cell Rep. 2017 Oct 3;21(1):60-69. doi: 10.1016/j.celrep.2017.09.023.
Wnt signaling controls multiple biological process, particularly the embryonic development of metazoans. Sustained expression of Wnt signaling components in the mature mammalian CNS and their apparent deregulation in certain neuropathologies suggest that it also plays a part beyond embryonic development to regulate normal brain function. We describe a noncanonical Wnt/Ca signaling cascade that regulates the electrophysiological intrinsic properties of rat neurons, resulting in sustained membrane depolarization and the mobilization of Ca from internal stores. These effects require tyrosine kinase-like orphan receptor 2 (RoR2), activation of PLC, and voltage-gated Ca channels. Activation of this signaling cascade then promotes surface expression of N-methyl-D-aspartate receptors (NMDARs) through a SNARE-dependent mechanism. This neuronal Wnt/Ca signaling pathway represents a mechanism for Wnt ligands to regulate normal brain processes in the mature animal and provides a framework for understanding how alterations in this pathway may contribute to the etiology of psychiatric disorders where NMDARs are compromised.
Wnt 信号通路控制着多种生物学过程，特别是后生动物的胚胎发育。成熟哺乳动物中枢神经系统中 Wnt 信号通路成分的持续表达及其在某些神经病理学中的明显失调表明，它在胚胎发育之外也发挥作用，以调节正常的大脑功能。我们描述了一个非典型的 Wnt/Ca 信号级联反应，它调节大鼠神经元的电生理固有特性，导致膜持续去极化和内部储存的 Ca 动员。这些效应需要酪氨酸激酶样孤儿受体 2（RoR2）、PLC 的激活和电压门控 Ca 通道。该信号级联的激活随后通过 SNARE 依赖性机制促进 N-甲基-D-天冬氨酸受体（NMDARs）的表面表达。这种神经元 Wnt/Ca 信号通路代表了 Wnt 配体在成熟动物中调节正常大脑过程的一种机制，并为理解该通路的改变如何导致 NMDAR 受损的精神疾病的病因提供了框架。
