<br>培养的星形胶质细胞中 G 蛋白信号转导 4 （RGS4）调节剂调节 5 型代谢型谷氨酸受体介导的细胞内钙动员,Cells

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培养的星形胶质细胞中 G 蛋白信号转导 4 （RGS4）调节剂调节 5 型代谢型谷氨酸受体介导的细胞内钙动员
Cells ( IF 5.1 ) Pub Date : 2024-02-06 , DOI: 10.3390/cells13040291
Pauline Beckers ₁ , Pierre J Doyen ₁ , Emmanuel Hermans ₁

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G 蛋白信号转导（RGS）的调节因子作为 GTP 酶激活蛋白，促进活化的 G 蛋白沉默，通常被认为是细胞信号转导的负调节剂。在 CNS 中，RGS4 的表达在多种病理中发生改变，并且在暴露于炎症环境的星形胶质细胞中报道其上调。在培养的皮质星形胶质细胞模型中，我们在此研究了 RGS4 对 5 型代谢型谷氨酸受体（mGluR5）介导的细胞内钙信号传导的影响，已知该受体支持神经元和神经胶质细胞之间的双向通讯。通过暴露于抑制剂 CCG 63802 或用旨在实现 RGS4 沉默或过表达的慢病毒感染细胞来操纵 RGS4 活性。RGS4 的药理学抑制或沉默导致对 mGluR5 激动剂 DHPG 反应的细胞百分比和显示典型钙振荡的细胞比例降低。相反，RGS4 慢病毒感染增加了显示钙振荡的细胞百分比。虽然星形胶质细胞中胞质钙振荡的生理意义仍在研究中，但钙信号传导的微调可能决定了不同生物事件的编码。间接信号调节剂（如 RGS4 抑制剂）与受体配体联合使用，可以为各种神经系统疾病的新治疗方法铺平道路，提高疗效和选择性。

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Modulation of Type 5 Metabotropic Glutamate Receptor-Mediated Intracellular Calcium Mobilization by Regulator of G Protein Signaling 4 (RGS4) in Cultured Astrocytes

Acting as GTPase activating proteins promoting the silencing of activated G-proteins, regulators of G protein signaling (RGSs) are generally considered negative modulators of cell signaling. In the CNS, the expression of RGS4 is altered in diverse pathologies and its upregulation was reported in astrocytes exposed to an inflammatory environment. In a model of cultured cortical astrocytes, we herein investigate the influence of RGS4 on intracellular calcium signaling mediated by type 5 metabotropic glutamate receptor (mGluR5), which is known to support the bidirectional communication between neurons and glial cells. RGS4 activity was manipulated by exposure to the inhibitor CCG 63802 or by infecting the cells with lentiviruses designed to achieve the silencing or overexpression of RGS4. The pharmacological inhibition or silencing of RGS4 resulted in a decrease in the percentage of cells responding to the mGluR5 agonist DHPG and in the proportion of cells showing typical calcium oscillations. Conversely, RGS4-lentivirus infection increased the percentage of cells showing calcium oscillations. While the physiological implication of cytosolic calcium oscillations in astrocytes is still under investigation, the fine-tuning of calcium signaling likely determines the coding of diverse biological events. Indirect signaling modulators such as RGS4 inhibitors, used in combination with receptor ligands, could pave the way for new therapeutic approaches for diverse neurological disorders with improved efficacy and selectivity.

更新日期：2024-02-06

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