GPR30 介导的雌激素对肌动蛋白聚合和空间记忆的调节涉及到雌性小鼠海马中的 SRC-1 和 PI3K-mTORC2。
GPR30-mediated estrogenic regulation of actin polymerization and spatial memory involves SRC-1 and PI3K-mTORC2 in the hippocampus of female mice.
机构信息
Department of Neurobiology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing, China.
Department of Histology and Embryology, Third Military Medical University, Chongqing, China.
出版信息
CNS Neurosci Ther. 2019 Jun;25(6):714-733. doi: 10.1111/cns.13108. Epub 2019 Feb 3.
AIMS
The G-protein-coupled estrogen receptor GPR30 (also referred to as GPER) has been implicated in the estrogenic regulation of hippocampal plasticity and spatial memory; however, the molecular mechanisms are largely unclear.
METHODS
In this study, we initially examined the levels of GPR30 in the hippocampus of postnatal, ovariectomy (OVX)- and letrozole (LET)-treated female mice. Under G1, G15, and/or OVX treatment, the spatial memory, spine density, levels of ERα, ERβ, and SRC-1, selected synaptic proteins, mTORC2 signals (Rictor and p-AKT Ser473), and actin polymerization dynamics were subsequently evaluated. Furthermore, G1, G15, and/or E2 combined with SRC-1 and/or PI3K inhibitors, actin cytoskeleton polymerization modulator JPK, and CytoD treatments were used to address the mechanisms that underlie GPR30 regulation in vitro. Finally, mTORC2 activator A-443654 (A4) was used to explore the role of mTORC2 in GPR30 regulation of spatial memory.
RESULTS
The results showed that high levels of GPR30 were detected in the adult hippocampus and the levels were downregulated by OVX and LET. OVX induced an impairment of spatial memory, and changes in other parameters previously described were reversed by G1 and mimicked by G15. Furthermore, the E2 effects on SRC-1 and mTORC2 signals, synaptic proteins, and actin polymerization were inhibited by G15, whereas G1 effects on these parameters were inhibited by the blockade of SRC-1 or PI3K; the levels of synaptic proteins were regulated by JPK and CytoD. Importantly, G15-induced actin depolymerization and spatial memory impairment were rescued by mTORC2 activation with A4.
CONCLUSIONS
Taking together, these results demonstrated that decreased GPR30 induces actin depolymerization through SRC-1 and PI3K/mTORC2 pathways and ultimately impairs learning and memory, indicating its potential role as a therapeutic target against hippocampus-based, E2-related memory impairments.
目的
G 蛋白偶联雌激素受体 GPR30（也称为 GPER）已被牵涉到海马体可塑性和空间记忆的雌激素调节中；然而，其分子机制在很大程度上仍不清楚。
方法
在这项研究中，我们最初检查了新生、去卵巢（OVX）和来曲唑（LET）处理的雌性小鼠海马体中的 GPR30 水平。在 G1、G15 和/或 OVX 处理下，随后评估了空间记忆、棘突密度、ERα、ERβ 和 SRC-1 水平、选定的突触蛋白、mTORC2 信号（Rictor 和 p-AKT Ser473）和肌动蛋白聚合动力学。此外，使用 G1、G15 和/或 E2 与 SRC-1 和/或 PI3K 抑制剂、肌动蛋白细胞骨架聚合调节剂 JPK 和 CytoD 处理来解决体外 GPR30 调节的机制。最后，使用 mTORC2 激活剂 A-443654（A4）来探索 mTORC2 在 GPR30 调节空间记忆中的作用。
结果
结果表明，成年海马体中检测到高水平的 GPR30，其水平被 OVX 和 LET 下调。OVX 诱导空间记忆受损，而先前描述的其他参数的变化被 G1 和 G15 逆转。此外，E2 对 SRC-1 和 mTORC2 信号、突触蛋白和肌动蛋白聚合的作用被 G15 抑制，而 G1 对这些参数的作用被 SRC-1 或 PI3K 阻断抑制；突触蛋白的水平受 JPK 和 CytoD 调节。重要的是，用 A4 激活 mTORC2 可挽救 G15 诱导的肌动蛋白解聚和空间记忆损伤。
结论
总的来说，这些结果表明，GPR30 减少通过 SRC-1 和 PI3K/mTORC2 途径诱导肌动蛋白解聚，最终损害学习和记忆，表明其作为治疗与海马体相关的雌激素相关记忆损伤的潜在靶点的作用。
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