Sigma 1 Receptor and Ion Channel Dynamics in Cancer

Soriani, Olivier; Rapetti-Mauss, Raphaël

doi:10.1007/978-3-319-50174-1_6

Cited by 16 publications

(14 citation statements)

References 80 publications

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“…It has been characterized as a molecular chaperone in the endoplasmic reticulum (ER) (Hayashi and Su, 2007), and may be a promising therapeutic target for several neuropsychiatric disorders (Kourrich et al, 2012; Maurice and Su, 2009). In addition, σ 1 R has been shown to be involved in pain (Romero et al, 2016; Sanchez-Fernandez et al, 2017), psychostimulant abuse (Katz et al, 2017; Sabino et al, 2017), and neurodegenerative diseases (Maurice and Goguadze, 2017; Nguyen et al, 2017) among others (Albayrak and Hashimoto, 2017; Soriani and Rapetti-Mauss, 2017; Wang et al, 2017). Depending on the physiological readout, σ 1 R ligands have been described as “agonists” or “antagonists”, as for G-protein coupled receptors (GPCRs).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological profiling of sigma 1 receptor ligands by novel receptor homomer assays

Yano

Bonifazi

et al. 2018

Neuropharmacology

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The sigma 1 receptor (σR) is a structurally unique transmembrane protein that functions as a molecular chaperone in the endoplasmic reticulum (ER), and has been implicated in cancer, neuropathic pain, and psychostimulant abuse. Despite physiological and pharmacological significance, mechanistic underpinnings of structure-function relationships of σR are poorly understood, and molecular interactions of selective ligands with σR have not been elucidated. The recent crystallographic determination of σR as a homo-trimer provides the foundation for mechanistic elucidation at the molecular level. Here we report novel bioluminescence resonance energy transfer (BRET) assays that enable analyses of ligand-induced multimerization of σR and its interaction with BiP. Haloperidol, PD144418, and 4-PPBP enhanced σR homomer BRET signals in a dose dependent manner, suggesting their significant effects in stabilizing σR multimerization, whereas (+)-pentazocine and several other ligands do not. In non-denaturing gels, (+)-pentazocine significantly decreased whereas haloperidol increased the fraction of σR multimers, consistent with the results from the homomer BRET assay. Further, BRET assays examining heteromeric σR-BiP interaction revealed that (+)-pentazocine and haloperidol induced opposite trends of signals. From molecular modeling and simulations of σR in complex with the tested ligands, we identified initial clues that may lead to the differed responses of σR upon binding of structurally diverse ligands. By combining multiple in vitro pharmacological and in silico molecular biophysical methods, we propose a novel integrative approach to analyze σR-ligand binding and its impact on interaction of σR with client proteins.

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Section: Introductionmentioning

confidence: 99%

Pharmacological profiling of sigma 1 receptor ligands by novel receptor homomer assays

Yano

Bonifazi

et al. 2018

Neuropharmacology

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“…Together, these data suggest that S1R participates in the formation of ion channel complexes in cancer tissues and may represent a promising candidate to target ion channel-dependent signalling in cancers (Soriani and Rapetti-Mauss, 2017).…”

Section: Regulation By the Sigma-1 Receptor Chaperonementioning

confidence: 74%

Potassium and Calcium Channel Complexes as Novel Targets for Cancer Research

Potier-Cartereau

Raoul

Weber

et al. 2020

Reviews of Physiology, Biochemistry and Pharmacology

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The intracellular Ca 2+ concentration is mainly controlled by Ca 2+ channels. These channels form complexes with K + channels, which function to amplify Ca 2+ flux. In cancer cells, voltage-gated/voltage-dependent Ca 2+ channels and non-voltage-gated/voltage-independent Ca 2+ channels have been reported to interact with K + channels such as Ca 2+-activated K + channels and voltage-gated K + channels. These channels are activated by an increase in cytosolic Ca 2+ concentration or by membrane depolarisation, which induces membrane hyperpolarisation, increasing the driving force for Ca 2+ flux. These complexes, composed of K + and Ca 2+ channels, are regulated by several molecules including lipids (ether-lipids and cholesterol), proteins (e.g., STIM), receptors (e.g., S1R/SIGMAR1) and peptides (e.g., LL-37), and can be targeted by monoclonal antibodies, making them novel targets for cancer research.

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“…Altogether, these results suggest that σ1R plays a significant role in cancer cell by regulating ion channel-related mechanisms (e.g., AVD, RVD, integrin signaling, Ca 2+ homeostasis) (Aydar et al, 2016; Crottès et al, 2016; Guéguinou et al, 2016; Soriani and Rapetti-Mauss, 2017; Rapetti-Mauss et al, 2018).…”

Section: σ1r:ion Channels In Chronic Diseases: Stimulant Addiction Anmentioning

confidence: 94%

“…Furthermore, while emerging evidence suggest that some channel family-specific auxiliary subunits have the ability to regulate ion channels from other superfamilies, such as the Na + channel auxiliary subunits Na v β modulating voltage-gated K + channels (Marionneau et al, 2012; Calhoun and Isom, 2014), this feature is extended and even exacerbated in σ1R. In particular, σ1R regulates via direct protein-protein interactions the functions of all VGIC superfamilies (i.e., Na + , Ca 2+ , and K + families) and classes (i.e., ligand-gated ion channels, e.g., NMDA receptors, NMDARs; and G protein-coupled receptors, e.g., dopamine receptors, DARs) (reviewed in Crottès et al, 2013; Kourrich, 2017; Soriani and Rapetti-Mauss, 2017; Schmidt and Kruse, 2019). This unique characteristic positions σ1R as a powerful regulator of various cellular functions and neuronal excitability.…”

Section: σ1r-dependent Regulation Of Ion Channelsmentioning

confidence: 99%

The Sigma-1 Receptor: When Adaptive Regulation of Cell Electrical Activity Contributes to Stimulant Addiction and Cancer

Soriani

Kourrich

2019

Front. Neurosci.

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The sigma-1 receptor (σ1R) is an endoplasmic reticulum (ER)-resident chaperone protein that acts like an inter-organelle signaling modulator. Among its several functions such as ER lipid metabolisms/transports and indirect regulation of genes transcription, one of its most intriguing feature is the ability to regulate the function and trafficking of a variety of functional proteins. To date, and directly relevant to the present review, σ1R has been found to regulate both voltage-gated ion channels (VGICs) belonging to distinct superfamilies (i.e., sodium, Na+; potassium, K+; and calcium, Ca2+ channels) and non-voltage-gated ion channels. This regulatory function endows σ1R with a powerful capability to fine tune cells’ electrical activity and calcium homeostasis—a regulatory power that appears to favor cell survival in pathological contexts such as stroke or neurodegenerative diseases. In this review, we present the current state of knowledge on σ1R’s role in the regulation of cellular electrical activity, and how this seemingly adaptive function can shift cell homeostasis and contribute to the development of very distinct chronic pathologies such as psychostimulant abuse and tumor cell growth in cancers.

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Sigma 1 Receptor and Ion Channel Dynamics in Cancer

Cited by 16 publications

References 80 publications

Pharmacological profiling of sigma 1 receptor ligands by novel receptor homomer assays

Pharmacological profiling of sigma 1 receptor ligands by novel receptor homomer assays

Potassium and Calcium Channel Complexes as Novel Targets for Cancer Research

The Sigma-1 Receptor: When Adaptive Regulation of Cell Electrical Activity Contributes to Stimulant Addiction and Cancer

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