Sigma-1 receptor directly interacts with Rac1-GTPase in the brain mitochondria.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Institute of Chemical Biology, Ilia State University, 3/5 Cholokashvili av, Tbilisi, 0162, Georgia. nino_natsvlishvili@iliauni.edu.ge.|Department of Biochemistry, I.Beritashvili Center of Experimental Biomedicine, 14 Gotua st, Tbilisi, 0160, Georgia. nino_natsvlishvili@iliauni.edu.ge.
Nino
N
Natsvlishvili
Institute of Chemical Biology, Ilia State University, 3/5 Cholokashvili av, Tbilisi, 0162, Georgia. nino.goguadze.2@iliauni.edu.ge.
Nino
N
Goguadze
Institute of Chemical Biology, Ilia State University, 3/5 Cholokashvili av, Tbilisi, 0162, Georgia. elene_zhuravliova@iliauni.edu.ge.|Department of Biochemistry, I.Beritashvili Center of Experimental Biomedicine, 14 Gotua st, Tbilisi, 0160, Georgia. elene_zhuravliova@iliauni.edu.ge.
Elene
E
Zhuravliova
Institute of Chemical Biology, Ilia State University, 3/5 Cholokashvili av, Tbilisi, 0162, Georgia. davit_mikeladze@iliauni.edu.ge.|Department of Biochemistry, I.Beritashvili Center of Experimental Biomedicine, 14 Gotua st, Tbilisi, 0160, Georgia. davit_mikeladze@iliauni.edu.ge.
David
D
Mikeladze
D000818:Animals; D001921:Brain / Q000166:cytology*; D002417:Cattle; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D000097605:Sigma-1 Receptor
D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019253:Proto-Oncogene Proteins c-bcl-2; D017480:Receptors, sigma; D020830:rac1 GTP-Binding Protein; D000097605:Sigma-1 Receptor