PDF(Pubmed)
Abstract：
Neuregulins (NRGs) signal via ErbB receptors to regulate neural development, excitability, synaptic and network activity, and behaviors relevant to psychiatric disorders. Bidirectional signaling between NRG2/ErbB4 and NMDA receptors is thought to homeostatically regulate GABAergic interneurons in response to increased excitatory neurotransmission or elevated extracellular glutamate levels. Unprocessed proNRG2 forms discrete clusters on cell bodies and proximal dendrites that colocalize with the potassium channel Kv2.1 at specialized endoplasmic reticulum-plasma membrane (ER-PM) junctions, and NMDA receptor activation triggers rapid dissociation from ER-PM junctions and ectodomain shedding by ADAM10. Here, we elucidate the mechanistic basis of proNRG2 clustering at ER-PM junctions and its regulation by NMDA receptors. Importantly, we demonstrate that proNRG2 promotes the formation of ER-PM junctions by directly binding the ER-resident membrane tether VAP, like Kv2.1. The proNRG2 intracellular domain harbors two non-canonical, low-affinity sites that cooperatively mediate VAP binding. One of these is a cryptic and phosphorylation-dependent VAP binding motif that is dephosphorylated following NMDA receptor activation, thus revealing how excitatory neurotransmission promotes the dissociation of proNRG2 from ER-PM junctions. Therefore, proNRG2 and Kv2.1 can independently function as VAP-dependent organizers of neuronal ER-PM junctions. Based on these and prior studies, we propose that proNRG2 and Kv2.1 serve as co-regulated downstream effectors of NMDA receptors to homeostatically regulate GABAergic interneurons.
摘要：
神经调节蛋白（NRGs）通过ErbB受体信号调节神经发育，兴奋性，突触和网络活动，以及与精神疾病相关的行为。NRG2/ErbB4和NMDA受体之间的双向信号传导被认为响应于增加的兴奋性神经传递或升高的细胞外谷氨酸水平而稳态调节GABA能中间神经元。未加工的proNRG2在细胞体和近端树突上形成离散的簇，与钾通道Kv2.1在专门的内质网-质膜（ER-PM）连接处共定位，和NMDA受体激活触发从ER-PM连接的快速解离和通过ADAM10的胞外域脱落。这里,我们阐明了proNRG2在ER-PM连接处聚集及其通过NMDA受体调节的机制基础。重要的是,我们证明proNRG2通过直接结合ER-驻留膜系链VAP促进ER-PM连接的形成，像Kv2.1.proNRG2细胞内结构域包含两个非规范的，协同介导VAP结合的低亲和力位点。其中之一是在NMDA受体激活后去磷酸化的隐匿性和磷酸化依赖性VAP结合基序，从而揭示兴奋性神经传递如何促进proNRG2从ER-PM连接的解离。因此,proNRG2和Kv2.1可以独立地充当神经元ER-PM连接的VAP依赖性组织者。基于这些和先前的研究，我们建议proNRG2和Kv2.1作为NMDA受体的共同调节下游效应子，以稳态调节GABA能中间神经元。
