Structural Insights into Sigma1 Function

Kruse, Andrew C.

doi:10.1007/164_2016_95

Cited by 15 publications

(17 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These classifications may be inaccurate, as Sigma1 is not a bona fide receptor. Sigma1 has been associated with myriad signaling and transduction systems largely through studies with these ligands (Kruse, 2016; Sabino and Cottone, 2016; Katz et al, 2017; Kim, 2017; Kim and Maher, 2017; Kourrich, 2017; Kruse, 2017; Laurini et al, 2017; Maurice and Goguadze, 2017; Merlos et al, 2017; Pasternak, 2017; Weber and Wunsch, 2017; Zeng et al, 2017). However, Sigma1 has no known intrinsic activity, and a preponderance of evidence suggests that it exerts its actions through allosteric modulation of other proteins and signaling systems (Hayashi and Su, 2007; Maurice and Su, 2009; Kim and Maher, 2017; Pasternak, 2017).…”

Section: Putative Agonists and Antagonists Of Sigma1 And Sigma2/tmem97mentioning

confidence: 99%

Small-Molecule Modulators of Sigma1 and Sigma2/TMEM97 in the Context of Cancer: Foundational Concepts and Emerging Themes

2019

View full text Add to dashboard Cite

There are two known subtypes of the so-called sigma receptors, Sigma1 and Sigma2. Sigma1 (encoded by the SIGMAR1 gene and also known as Sigma-1 receptor, S1R) is a unique pharmacologically regulated integral membrane chaperone or scaffolding protein that allosterically modulates the activity of its associated proteins. Sigma2, recently identified as transmembrane protein 97 (TMEM97), is an integral membrane protein implicated in cellular cholesterol homeostasis. A number of publications over the past two decades have suggested a role for both sigma proteins in tumor biology. Although there is currently no clinically used anti-cancer drug that targets Sigma1 or Sigma2/TMEM97, a growing body of evidence supports the potential of small-molecule compounds with affinity for these proteins, putative sigma ligands, as therapeutic agents to treat cancer. In preclinical models, these compounds have been reported to inhibit cancer cell proliferation, survival, adhesion, and migration; furthermore, they have been demonstrated to suppress tumor growth, to alleviate cancer-associated pain, and to exert immunomodulatory properties. Here, we will address the known knowns and the known unknowns of Sigma1 and Sigma2/TMEM97 ligand actions in the context of cancer. This review will highlight key discoveries and published evidence in support of a role for sigma proteins in cancer and will discuss several fundamental questions regarding the physiological roles of sigma proteins in cancer and sigma ligand mechanism of action.

show abstract

Section: Putative Agonists and Antagonists Of Sigma1 And Sigma2/tmem97mentioning

confidence: 99%

Small-Molecule Modulators of Sigma1 and Sigma2/TMEM97 in the Context of Cancer: Foundational Concepts and Emerging Themes

2019

View full text Add to dashboard Cite

show abstract

“…2), thus raising the hypothesis that the receptor could regulate the expression and/or the function of cell-surface receptors. Kruse recently reviewed the intriguing features of this protein that shows no structural resemblance with any other membrane receptor, that has an occluded ligand-binding site and that resembles a yeast enzyme, yeast sterol isomerase (Kruse 2017). Remarkably, while the physiological function remains elusive and the endogenous ligand is yet to be discovered, cocaine binds to σ 1 R (Skuza 1999, Shull 2002, Lever et al 2016.…”

Section: Evidence For a Relevant Role Of σ 1 R On Cocaine Addictionmentioning

confidence: 99%

The sigma-1 receptor as key common factor in cocaine and food-seeking behaviors

Aguinaga

Casanovas

Rivas‐Santisteban

et al. 2019

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

Addiction and eating disorders involve brain reward circuits. Binge eating predisposes to addictive behavior, while the cessation of exposure to drugs of abuse leads to reward activities, including intake of tasty foods. Cocaine use is associated with a decrease in food intake, with reversal after drug use is discontinued. Exciting new findings show that receptors for the ‘hunger’ hormone, ghrelin, directly interact with the sigma-1 receptor (σ1R), which is a target of cocaine. σ1Rs are key players in regulating dopaminergic neurotransmission and ghrelin-mediated actions. This review focuses on the σ1 receptor as a general neuroendocrine regulator by directly interacting with neuronal G-protein-coupled receptors. This review also covers the early mechanisms by which cocaine binding to σ1 blocks the food-seeking behavior triggered by ghrelin. Those findings appear as fundamental to understand common mechanisms in drug addiction and eating disorders.

show abstract

“…It was determined that its sequence shares no homology with any other mammalian protein, that it contains a typical ER-retention signal within the N-terminus and, initial hydrophobicity analysis, provided the first sign of the presence of a single transmembrane segment (Hanner et al, 1996). Also, it was defined that the C-terminus of this receptor (residues 33–223) contains the ligand binding-sites (Kruse, 2017), two steroid-like binding domains (SBDL1-2) (Pal et al, 2007) and the chaperone domain (Figure 1; Hayashi and Su, 2007; Ortega-Roldan et al, 2013). Another essential feature of Sig-1R is its intracellular mobility, although it is mostly localized to the mitochondria-associated membrane (MAM) of the ER (a domain with high cholesterol content; Hayashi and Su, 2007), it still exhibits movement toward the plasma membrane and nuclear envelope (Hayashi and Su, 2003).…”

Section: Introductionmentioning

confidence: 99%

Molecular Interplay Between the Sigma-1 Receptor, Steroids, and Ion Channels

2019

View full text Add to dashboard Cite

Cell excitability is tightly regulated by the activity of ion channels that allow for the passage of ions across cell membranes. Ion channel activity is controlled by different mechanisms that change their gating properties, expression or abundance in the cell membrane. The latter can be achieved by forming complexes with a diversity of proteins like chaperones such as the Sigma-1 receptor (Sig-1R), which is one with unique features and exhibits a role as a ligand-operated chaperone. This molecule also displays high intracellular mobility according to its activation level since, depletion of internal Ca +2 stores or the presence of specific ligands, produce Sig-1R’s mobilization from the endoplasmic reticulum toward the plasma membrane or nuclear envelope. The function of the Sig-1R as a chaperone is regulated by synthetic and endogenous ligands, with some of these compounds being a steroids and acting as key endogenous modifiers of the actions of the Sig-1R. There are cases in the literature that exemplify the close relationship between the actions of steroids on the Sig-1R and the resulting negative or positive effects on ion channel function/abundance. Such interactions have been shown to importantly influence the physiology of mammalian cells leading to changes in their excitability. The present review focuses on describing how the Sig-1R regulates the functional properties and the expression of some sodium, calcium, potassium, and TRP ion channels in the presence of steroids and the physiological consequences of these interplays at the cellular level are also discussed.

show abstract

Structural Insights into Sigma1 Function

Cited by 15 publications

References 41 publications

Small-Molecule Modulators of Sigma1 and Sigma2/TMEM97 in the Context of Cancer: Foundational Concepts and Emerging Themes

Small-Molecule Modulators of Sigma1 and Sigma2/TMEM97 in the Context of Cancer: Foundational Concepts and Emerging Themes

The sigma-1 receptor as key common factor in cocaine and food-seeking behaviors

Molecular Interplay Between the Sigma-1 Receptor, Steroids, and Ion Channels

Contact Info

Product

Resources

About