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

Natsvlishvili, Nino; Goguadze, Nino; Zhuravliova, Elene; Mikeladze, David

doi:10.1186/s12858-015-0040-y

Cited by 60 publications

(49 citation statements)

References 34 publications

(50 reference statements)

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“…Recently, Natsvlishvili et al . [51] reported that, by using immunoprecipitation, the Sig-1R not only directly interacts with Rac1-GTPase, but also forms complexes with IP3R, BiP, and Bcl2, in the brain mitochondria. Interestingly, the ligand-specific assembly complex relies on the Sig-1R agonist/antagonist and the presence of GTP/GDP.…”

Section: Sig-1r–interacting Proteins Per Experimental Demonstrations mentioning

confidence: 99%

The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems

Nakamura

et al. 2016

Trends in Pharmacological Sciences

260

257

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The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum (ER) protein resides specifically at the interface between ER and mitochondria, called the MAM, where the Sig-1R is recently reported to be involved in certain CNS diseases. In addition to being able to translocate to the plasma membrane to interact with ion channels and other receptors, the Sig-1R is found to exist at the nuclear envelope where it recruits chromatin-remodeling factors to affect the transcription of genes. As well, thorough experimental and bioinformatic means, Sig-1Rs are reported to interact with other membranous or soluble proteins at other loci, including the cytosol. We propose that the Sig-1R is a pluripotent modulator with resultant multiple functional manifestations in the living system.

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Section: Sig-1r–interacting Proteins Per Experimental Demonstrations mentioning

confidence: 99%

The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems

Nakamura

et al. 2016

Trends in Pharmacological Sciences

260

257

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“…Navarro et al (2010) have also been reported. The S1R directly and indirectly modulates neuronal mitochondrial Rac-1 GTPase (Tsai et al, 2009;Natsvlishvili et al, 2015), which is involved in dendritic spine formation. S1R reduces tau phosphorylation (Tsai et al, 2015) via indirect regulation of cyclin-dependent kinase 5 (cdk5) and thus protects neuronal axon elongation.…”

Section: Introductionmentioning

confidence: 99%

Biochemical Pharmacology of the Sigma-1 Receptor

2015

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The sigma-1 receptor (S1R) is a 223 amino acid two transmembrane (TM) pass protein. It is a non-ATP-binding nonglycosylated ligand-regulated molecular chaperone of unknown three-dimensional structure. The S1R is resident to eukaryotic mitochondrial-associated endoplasmic reticulum and plasma membranes with broad functions that regulate cellular calcium homeostasis and reduce oxidative stress. Several multitasking functions of the S1R are underwritten by chaperone-mediated direct (and indirect) interactions with ion channels, G-protein coupled receptors and cell-signaling molecules involved in the regulation of cell growth. The S1R is a promising drug target for the treatment of several neurodegenerative diseases related to cellular stress. In vitro and in vivo functional and molecular characteristics of the S1R and its interactions with endogenous and synthetic small molecules have been discovered by the use of pharmacologic, biochemical, biophysical, and molecular biology approaches. The S1R exists in monomer, dimer, tetramer, hexamer/octamer, and higher oligomeric forms that may be important determinants in defining the pharmacology and mechanism(s) of action of the S1R. A canonical GXXXG in putative TM2 is important for S1R oligomerization. The ligand-binding regions of S1R have been identified and include portions of TM2 and the TM proximal regions of the C terminus. Some client protein chaperone functions and interactions with the cochaperone 78-kDa glucose-regulated protein (binding immunoglobulin protein) involve the C terminus. Based on its biochemical features and mechanisms of chaperone action the possibility that the S1R is a member of the small heat shock protein family is discussed.

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“…However, the anti-oxidative stress function was abolished when Sig1-R was knocked out (Pal et al 2012). Sig1-R can also regulate the production of ROS through the ER-mitochondrial Rac1 system, and this system could promote a mild pro-oxidant milieu for cellular signaling and induce plastic transformation in neurons (Natsvlishvili et al 2015). 4-Phenyl-1-(4-phenylbutyl) piperidine (PPBP), a Sig1-R agonist, could protect neurons via a mechanism that involves the antiapoptotic protein Bcl-2 (Yang et al 2007).…”

Section: Sig1-rmentioning

confidence: 99%

Potential Roles of Mitochondria-Associated ER Membranes (MAMs) in Traumatic Brain Injury

Sun

Chen

et al. 2017

Cell Mol Neurobiol

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The endoplasmic reticulum (ER) and mitochondria have both been shown to be critical in cellular homeostasis. The functions of the ER and mitochondria are independent but interrelated. These two organelles could form physical interactions, known as MAMs, to regulate physiological functions between ER and mitochondria to maintain Ca, lipid, and metabolite exchange. Several proteins are located in MAMs, including RNA-dependent protein kinase (PKR)-like ER kinase, inositol 1,4,5-trisphosphate receptors, phosphofurin acidic cluster sorting protein-2 and sigma-1 receptor to ensure regulation. Recent studies indicated that MAMs participate in inflammation and apoptosis in various conditions. All of these functions are crucial in determining cell fate following traumatic brain injury (TBI). We hypothesized that MAMs may associate with TBI and could contribute to mitochondrial dysfunction, ER stress, autophagy dysregulation, dysregulation of Ca homeostasis, and oxidative stress. In this review, we summarize the latest understanding of MAM formation and their potential regulatory role in TBI pathophysiology.

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

Cited by 60 publications

References 34 publications

The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems

The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems

Biochemical Pharmacology of the Sigma-1 Receptor

Potential Roles of Mitochondria-Associated ER Membranes (MAMs) in Traumatic Brain Injury

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