title: Sig1R protein regulates hERG channel expression through a post-translational mechanism in leukemic cells.
abstract: Sig1R (Sigma-1receptor) is a 25-kDa protein structurally unrelated to other mammalian proteins. Sig1R is present in brain, liver, and heart and is overexpressed in cancer cells. Studies using exogenous sigma ligands have shown that Sig1R interacts with a variety of ion channels, but its intrinsic function and mechanism of action remain unclear. The human ether-à-gogo related gene (hERG) encodes a cardiac channel that is also abnormally expressed in many primary human cancers, potentiating tumor progression through the modulation of extracellular matrix adhesive interactions. We show herein that sigma ligands inhibit hERG current density and cell adhesion to fibronectin in K562 myeloid leukemia cells. Heterologous expression in Xenopus oocytes demonstrates that Sig1R potentiates hERG current by stimulating channel subunit biosynthesis. Silencing Sig1R in leukemic K562 cells depresses hERG current density and cell adhesion to fibronectin by reducing hERG membrane expression. In K562 cells, Sig1R silencing does not modify hERG mRNA contents but reduces hERG mature form densities. In HEK cells expressing hERG and Sig1R, both proteins co-immunoprecipitate, demonstrating a physical association. Finally, Sig1R expression enhances both channel protein maturation and stability. Altogether, these results demonstrate for the first time that Sig1R controls ion channel expression through the regulation of subunit trafficking activity.
authors.affiliation: CNRS, UMR 6543, Nice 06108 Cedex 2, France.
authors.forename: David
authors.initials: D
authors.lastname: Crottès
authors.forename: Sonia
authors.initials: S
authors.lastname: Martial
authors.forename: Raphaël
authors.initials: R
authors.lastname: Rapetti-Mauss
authors.forename: Didier F
authors.initials: DF
authors.lastname: Pisani
authors.forename: Céline
authors.initials: C
authors.lastname: Loriol
authors.forename: Bernard
authors.initials: B
authors.lastname: Pellissier
authors.forename: Patrick
authors.initials: P
authors.lastname: Martin
authors.forename: Eric
authors.initials: E
authors.lastname: Chevet
authors.forename: Franck
authors.initials: F
authors.lastname: Borgese
authors.forename: Olivier
authors.initials: O
authors.lastname: Soriani
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D017136:Ion Transport; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D017480:Receptors, sigma / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis; D000097605:Sigma-1 Receptor
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005353:Fibronectins; D009363:Neoplasm Proteins; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C000606913:KCNH2 protein, human