Natsvlishvili Nino, Goguadze Nino, Zhuravliova Elene, Mikeladze David
Institute of Chemical Biology, Ilia State University, 3/5 Cholokashvili av, Tbilisi, 0162, Georgia.
Department of Biochemistry, I.Beritashvili Center of Experimental Biomedicine, 14 Gotua st, Tbilisi, 0160, Georgia.
BMC Biochem. 2015 Apr 30;16:11. doi: 10.1186/s12858-015-0040-y.
Small Rho-GTPases are critical mediators of neuronal plasticity and are involved in the pathogenesis of several psychiatric and neurological disorders. Rac-GTPase forms a multiprotein complex with upstream and downstream regulators that are essential for the spatiotemporal transmission of Rac signaling. The sigma-1 receptor (Sig1R) is a ligand-regulated membrane protein chaperone, and multiprotein complex assembly is essential to sigma-receptor function.
Using immunoprecipitation techniques, we have shown that in mitochondrial membranes Sig1R could directly interact with Rac1. Besides Rac1, the Sig1R forms complexes with inositol 1,4,5-trisphosphate receptor and Bcl2, suggesting that mitochondrial associated membranes (MAM) are involved in this macromolecular complex formation. Assembly of this complex is ligand-specific and depends on the presence of sigma agonist/antagonist, as well as on the presence of GTP/GDP. Treatment of mitochondrial membranes with (+)-pentazocine leads to the (+)-pentazocine-sensitive phosphorylation of Bad and the pentazocine-sensitive NADPH-dependent production of ROS.
We suggest that Sig1R through Rac1 signaling induces mild oxidative stress that possibly is involved in the regulation of neuroplasticity, as well as in the prevention of apoptosis and autophagy.
小Rho-GTP酶是神经元可塑性的关键介质，参与多种精神和神经疾病的发病机制。Rac-GTP酶与上游和下游调节因子形成多蛋白复合物，这些调节因子对Rac信号的时空传递至关重要。sigma-1受体（Sig1R）是一种配体调节的膜蛋白伴侣，多蛋白复合物组装对sigma受体功能至关重要。
利用免疫沉淀技术，我们发现线粒体膜中的Sig1R可直接与Rac1相互作用。除Rac1外，Sig1R还与肌醇1,4,5-三磷酸受体和Bcl2形成复合物，提示线粒体相关膜（MAM）参与了这种大分子复合物的形成。这种复合物的组装具有配体特异性，依赖于sigma激动剂/拮抗剂的存在以及GTP/GDP的存在。用（+）-喷他佐辛处理线粒体膜会导致Bad的（+）-喷他佐辛敏感磷酸化以及喷他佐辛敏感的NADPH依赖性ROS产生。
我们认为Sig1R通过Rac1信号传导诱导轻度氧化应激，这可能参与神经可塑性的调节以及细胞凋亡和自噬的预防。
