A Direct Interaction between the Sigma-1 Receptor and the hERG Voltage-gated K+ Channel Revealed by Atomic Force Microscopy and Homogeneous Time-resolved Fluorescence (HTRF®)

Balasuriya, Dilshan; D'Sa, Lauren; Talker, Ronel; Dupuis, Elodie; Maurin, Fabrice; Martin, Patrick; Borgèse, Franck; Soriani, Olivier; Edwardson, J. Michael

doi:10.1074/jbc.m114.603506

Cited by 48 publications

(49 citation statements)

References 64 publications

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“…hERG recruitment following cell contact with ECM requires the presence of Sig1R that behaves as a chaperone driving hERG to the plasma membrane. In agreement with this hypothesis, we and others have shown that Sig1R directly binds with hERG and other ion channels, promoting their activity and their membrane expression (15,19,25). In the context of ECM stimulation, hERG current was increased without modifying channel maturation ratio (Supplementary Fig.…”

Section: Discussionsupporting

confidence: 65%

“…Therefore, Sig1R has been associated to many pathophysiologic contexts, including stroke, neurodegenerative diseases, pain, or cocaine addiction (15). Interestingly, Sig1R is overexpressed in cancer cell lines (23), and we have shown that it functions as a chaperone enhancing maturation and membrane expression of hERG by a direct physical interaction (24,25).…”

Section: Introductionmentioning

confidence: 95%

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SIGMAR1 Regulates Membrane Electrical Activity in Response to Extracellular Matrix Stimulation to Drive Cancer Cell Invasiveness

et al. 2016

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The sigma 1 receptor (Sig1R) is a stress-activated chaperone that regulates ion channels and is associated with pathologic conditions, such as stroke, neurodegenerative diseases, and addiction. Aberrant expression levels of ion channels and Sig1R have been detected in tumors and cancer cells, such as myeloid leukemia and colorectal cancer, but the link between ion channel regulation and Sig1R overexpression during malignancy has not been established. In this study, we found that Sig1R dynamically controls the membrane expression of the human voltage-dependent K þ channel human ether-a-go-go-related gene (hERG) in myeloid leukemia and colorectal cancer cell lines. Sig1R promoted the formation of hERG/b1-integrin signaling complexes upon extracellular matrix stimulation, triggering the activation of the PI3K/ AKT pathway. Consequently, the presence of Sig1R in cancer cells increased motility and VEGF secretion. In vivo, Sig1R expression enhanced the aggressiveness of tumor cells by potentiating invasion and angiogenesis, leading to poor survival. Collectively, our findings highlight a novel function for Sig1R in mediating crosstalk between cancer cells and their microenvironment, thus driving oncogenesis by shaping cellular electrical activity in response to extracellular signals. Given the involvement of ion channels in promoting several hallmarks of cancer, our study also offers a potential strategy to therapeutically target ion channel function through Sig1R inhibition. Cancer Res; 76(3); 607-18. Ó2015 AACR.

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Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 95%

SIGMAR1 Regulates Membrane Electrical Activity in Response to Extracellular Matrix Stimulation to Drive Cancer Cell Invasiveness

et al. 2016

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“…4). In agreement with these general ideas, using atomic force microscopy, Balasuriya et al (2012) have shown that the monomer form of the S1R (or possibly a monomer form generated from the dimer) has been identified as directly bound to the voltage-gated Na v 1.5 sodium channel with 4-fold symmetry, to the human ether-à-go-go (hERG) voltage-gated potassium channel (Balasuriya et al, 2014) with 4-fold symmetry, to the acid-sensing ion channel-1a with 3-fold symmetry (Carnally et al, 2010), and with selectivity to the GLuN1 subunit of the GluN1/GluN2a N-methyl-D-apartate receptor (Balasuriya et al, 2013) (see Table 3 for further examples of client proteins that have been shown to interact with the S1R).…”

Section: Biochemical Pharmacology Of the Sigma-1 Receptormentioning

confidence: 52%

“…However, because the S1R has been demonstrated to bind to the nonglycosylated form of the hERG channel at the plasma membrane (Balasuriya et al, 2014), questions remain as to whether the S1R binds to the semiunfolded state or the native form of these protein substrates as a functional subunit.…”

Section: Biochemical Pharmacology Of the Sigma-1 Receptormentioning

confidence: 99%

“…The molecular features of the membranebound S1R that show pharmacologic regulation via endogenous and synthetic small molecules place it in a unique niche of the superfamily of small heat shock protein chaperones. (Tchedre et al, 2008) hERG (Balasuriya et al, 2014) Other channels Acid-sensing ion channels (ASICs) (Carnally et al, 2010) Volume-regulated chloride channel (VRCC) (Renaudo et al, 2007) Inositol triphosphate receptor (IP 3 R) (Hayashi and Su, 2007) N-methyl-D-aspartate (NMDA) (GluN1) GPCRs (Balasuriya et al, 2013) Dopamine D1 (Navarro et al, 2010) m Opioid and muscarinic receptors (Kim et al, 2010) Others Ankyrin (Hayashi and Su, 2001) BiP (Hayashi and Su, 2007) Biochemical Pharmacology of the Sigma-1 Receptor…”

Section: Conclusion and Summarymentioning

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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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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A Direct Interaction between the Sigma-1 Receptor and the hERG Voltage-gated K+ Channel Revealed by Atomic Force Microscopy and Homogeneous Time-resolved Fluorescence (HTRF®)

Cited by 48 publications

References 64 publications

SIGMAR1 Regulates Membrane Electrical Activity in Response to Extracellular Matrix Stimulation to Drive Cancer Cell Invasiveness

SIGMAR1 Regulates Membrane Electrical Activity in Response to Extracellular Matrix Stimulation to Drive Cancer Cell Invasiveness

Biochemical Pharmacology of the Sigma-1 Receptor

Potassium and Calcium Channel Complexes as Novel Targets for Cancer Research

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