The sigma-1 receptors are present in monomeric and oligomeric forms in living cells in the presence and absence of ligands

Mishra, A. K.; Mavlyutov, Timur A.; Singh, Deo R.; Biener, Gabriel; Yang, Jay; Oliver, Julie A.; Ruoho, Arnold E.; Raicu, Valerică

doi:10.1042/bj20141321

Cited by 104 publications

(114 citation statements)

References 78 publications

(113 reference statements)

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“…It is therefore reasonable to consider the following scenario: monomer, dimer, tetramer, hexamer/octamer states of the S1R may have important consequences regarding the chaperone functions of the S1R. As previously described when COS cells containing the S1R were incubated with the S1R agonist (1)-pentazocine, the relative ratio of dimer and monomers increased (Mishra et al, 2015) whereas treatment of the cells with the S1R inhibitor haloperidol increased higher oligomeric forms. It is tempting to speculate that higher oligomeric forms of the S1R are functionally inactive.…”

Section: Do Antagonists Of the S1r Function As Inversementioning

confidence: 99%

“…As previously described in this review, in vitro and in vivo the S1R exists in oligomeric forms that appear to be modulated by (1)-pentazocine and by haloperidol (Gromek et al, 2014;Mishra et al, 2015). Based on current knowledge in the field, the S1R does not bind ATP, in contrast to many large mammalian chaperone-like heat shock proteins such as GRP78/BiP Hsp 70, and Hsp 90 (Hayashi and Su, 2007).…”

Section: Biochemical Pharmacology Of the Sigma-1 Receptormentioning

confidence: 99%

“…3B, ix) (Chu et al, 2013) (Brune et al, 2014). Because the S1R has been shown both in vitro and in vivo to exist in various oligomeric forms (Gromek et al, 2014;Mishra et al, 2015) it is not clear, at present, which forms are binding to (1)-pentazocine and which forms are binding to the photoprobes. Subtle structural changes in the ligand-binding regions in the various forms could underwrite the differences observed between the [ photolabeling.…”

Section: Structural Features Of the S1r Ligand-binding Regionmentioning

confidence: 99%

“…3B, ix) (Chu et al, 2013) and by in situ oxidative crosslinking of a C94A, M170C guinea pig S1R construct. Further, when the S1R was coexpressed in COS-7 cells as C-terminal fluorescent protein (GFP2 and CYP) fusion constructs and analyzed by Forster resonance energy transfer (spectral FRET) (Mishra et al, 2015), the S1R was shown to exist constitutively in monomeric and oligomeric forms. Compared with non-drug-treated controls, dimer and monomer forms were favored in the presence of the agonist (1)-pentazocine, whereas higher order oligomers were favored in the presence of the S1R antagonist haloperidol.…”

Section: Functions Of the S1r May Be Based On Its Oligomerization Statesmentioning

confidence: 99%

“…The S1R has been established as a therapeutic target for many neurodegenerative conditions in humans that involve various forms of cellular metabolic stress, including amyotrophic lateral sclerosis (Al-Saif et al, 2011;Mancuso et al, 2012;Mavlyutov et al, 2013Mavlyutov et al, , 2015Prause et al, 2013;Gromek et al, 2014;Fukunaga et al, 2015;Mishra et al, 2015), frontotemporal lobar dementia (Luty et al, 2010), Alzheimer disease (Feher et al, 2012;Yin et al, 2015), Parkinson disease (Mishina et al, 2005;Mori et al, 2012), retinal neurodegeneration (Smith et al, 2008;Mavlyutov et al, 2011;Shimazawa et al, 2015), addiction to drugs of abuse (Navarro et al, 2010;Nguyen et al, 2015), and psychiatric disorders (Tsai et al, 2014) (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Do Antagonists Of the S1r Function As Inversementioning

confidence: 99%

Section: Biochemical Pharmacology Of the Sigma-1 Receptormentioning

confidence: 99%

Section: Structural Features Of the S1r Ligand-binding Regionmentioning

confidence: 99%

Section: Functions Of the S1r May Be Based On Its Oligomerization Statesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Biochemical Pharmacology of the Sigma-1 Receptor

2015

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Structural Insights into Sigma1 Function

Kruse

2016

Sigma Proteins: Evolution of the Concept of Sigma Receptors

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Sigma1 (also known as this sigma-1 receptor) is an unusual and enigmatic transmembrane protein implicated in a diverse array of biological processes ranging from neurodegenerative disease to cancer. Despite decades of research, the molecular architecture of Sigma1 is only beginning to become clear. Recent work has established that Sigma1 is an oligomer, and crystallographic studies have now offered the first high-resolution views of its molecular structure. For the first time, these results provide a detailed framework to understand mutagenesis data and the molecular pharmacology of Sigma1 ligands. Structural data also raise new questions surrounding the mechanisms of ligand activity and the molecular basis for interactions between Sigma1 and other proteins. As Sigma1 research enters the structural era, the field is poised for new discoveries and reevaluation of old data and old models.

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Sigma-1 Receptor and Pain

Merlos

Romero

Zamanillo

et al. 2017

Handbook of Experimental Pharmacology

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There is a critical need for new analgesics acting through new mechanisms of action, which could increase the efficacy respect to existing therapies and/or reduce their unwanted effects. Current preclinical evidence supports the modulatory role of the sigma-1 receptor (σR) in nociception, mainly based on the pain-attenuated phenotype of σR knockout mice and on the antinociceptive effect exerted by σR antagonists on pain of different etiology, very consistently in neuropathic pain, but also in nociceptive, inflammatory, and visceral pain. σR is highly expressed in different pain areas of the CNS and the periphery, particularly dorsal root ganglia (DRG), and interacts and modulates the functionality of different receptors and ion channels. Accordingly, antinociceptive effects of σR antagonists both acting alone and in combination with other analgesics have been reported at both central and peripheral sites. At the central level, behavioral, electrophysiological, neurochemical, and molecular findings support a role for σR antagonists in inhibiting augmented excitability secondary to sustained afferent input. Moreover, the involvement of σR in mechanisms regulating pain at the periphery has been recently confirmed. Unlike opioids, σR antagonists do not modify normal sensory mechanical and thermal sensitivity thresholds but they exert antihypersensitivity effects (antihyperalgesic and antiallodynic) in sensitizing conditions, enabling the reversal of nociceptive thresholds back to normal values. These are distinctive features allowing σR antagonists to exert a modulatory effect specifically in pathophysiological conditions such as chronic pain.

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The sigma-1 receptors are present in monomeric and oligomeric forms in living cells in the presence and absence of ligands

Cited by 104 publications

References 78 publications

Biochemical Pharmacology of the Sigma-1 Receptor

Biochemical Pharmacology of the Sigma-1 Receptor

Structural Insights into Sigma1 Function

Sigma-1 Receptor and Pain

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