The Sigma-1 Receptor Binds to the Nav1.5 Voltage-gated Na+ Channel with 4-Fold Symmetry

Abstract

Background: The sigma-1 receptor modulates the activity of ion channels.Results: Atomic force microscopy imaging of complexes between sigma-1 receptors and Nav1.5 Na+ channels reveals a 4-fold symmetry.Conclusion: Each of the four sets of six transmembrane regions in Nav1.5 constitutes a sigma-1 receptor binding site.Significance: The sigma-1 receptor likely interacts with the transmembrane regions of its protein partners.

Sigma-1 receptors modulate neonatal Nav1.5 ion channels in breast cancer cell lines

“…Following the assay cells were labelled with calcein-AM in order to verify that each dish contained equivalent numbers of cells. A similar experiment was performed for cells transfected with a sigma-1 receptor silencing construct for 48 h compared to those cells transfected with a control plasmid with past findings using atomic force microscopy showing that sigma-1 receptors and Na v 1.5 form a complex with a fourfold symmetry (Balasuriya et al 2012). It is not yet known whether the interaction between sigma-1 receptor and nNa v 1.5 is direct (i.e., protein-protein) or indirect (e.g., involving a small intermediary molecule).…”

“…It has been established by many researchers that sigma-1 receptors are able to modulate ion channels in a variety of cell types (Aydar et al 2002;Lupardus et al 2000;Johannessen et al 2011). In particular, the sigma-1 receptor was found to regulate the current density of VGSCs in MDA-MB-231 cells (Balasuriya et al 2012). Here, we have demonstrated that modulation of sigma-1 receptors in BCa cell lines can partially affect their metastatic behaviour (with respect to adhesiveness) and that this effect could be mediated via functional nNa v 1.5 expression.…”

“…It is now well established that VGSC (nNa v 1.5) up-regulation occurs in metastatic BCa cells and this promotes the cells metastatic behaviour in vitro and in vivo Brackenbury et al 2007;Nelson et al 2015). Although the exact mechanism of sigma-1 receptor modulation of ion channels is not clear, it has been suggested that sigma-1 receptors form a complex with VGSCs (Balasuriya et al 2012). Given these facts, our hypotheses are (1) that sigma-1 receptors form a functional signalling complex with VGSCs in BCa cell lines and (2) that, through this complex, sigma-1 receptors are able to modulate VGSC plasma membrane expression and hence the cells' metastatic behaviour.…”

“…Modulation of the heart voltagegated Na + channel (Na v 1.5) by sigma-receptors was demonstrated and this could be an important pathway through which drugs could alter cardiac excitability and rhythmicity (Johannessen et al 2011). This was further corroborated by atomic force microscopy imaging of complexes between sigma-1 receptors and Na v 1.5 channels revealing a fourfold symmetry (Balasuriya et al 2012). In human breast cancer (BCa) MDA-MB-231 cells, which functionally express the voltage-gated sodium channel (VGSC) subtype Na v 1.5, sigma-1 receptor was found to regulate current density, suggesting a functional interaction between the two proteins (Balasuriya et al 2012).…”

“…This was further corroborated by atomic force microscopy imaging of complexes between sigma-1 receptors and Na v 1.5 channels revealing a fourfold symmetry (Balasuriya et al 2012). In human breast cancer (BCa) MDA-MB-231 cells, which functionally express the voltage-gated sodium channel (VGSC) subtype Na v 1.5, sigma-1 receptor was found to regulate current density, suggesting a functional interaction between the two proteins (Balasuriya et al 2012). Despite such advances, however, the exact cellular mechanism of sigma-1 receptor action is still unclear and further experiments are required to clarify their role in physiological and pathophysiological cell signalling (Tsai et al 2009).…”