Abstract
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.
Highlights
The Sigma-1 receptor (Sig-1R) is a protein mainly localized to the endoplasmic reticulum (ER), where it functions as a ligand-operated chaperone (Hayashi and Su, 2003, 2007)
Whole-cell recordings showed that Sig-1R knockdown and the addition of BD1063 or progesterone to cell cultures, reduced the current-densities evoked by capsaicin, indicating that negative regulation of Sig-1R, decreased the amount of TRPV1 localized to the plasma membrane
We found that Sig-1R interacts with the transmembrane domain of TRPV1, to what had been previously reported for Kv1.3 ion channels (Kinoshita et al, 2012)
Summary
The Sigma-1 receptor (Sig-1R) is a protein mainly localized to the endoplasmic reticulum (ER), where it functions as a ligand-operated chaperone (Hayashi and Su, 2003, 2007). 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 Sig1R is its intracellular mobility, 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). This review article will focus on our current understanding of how the interactions between Sig-1R and steroids regulate some ion channels such as voltage-gated potassium and sodium channels, NMDA receptors and TRP channels as well as on the resulting physiological effects of such interactions (Figure 2)
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