Molecular Interplay Between the Sigma-1 Receptor, Steroids, and Ion Channels

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.

Keywords: NMDA – receptor; Sig-1R; TRPV1; ion channels; progesterone; steroids; voltage-gated ion channel.

FIGURE 1

Sigma-1 receptor topology. Structural domains of a monomer of the Sig-1R are shown in different colors: N-terminus (green and blue), transmembrane segment (TM, blue), C-terminus (red), and the two Steroid Binding Domain-Like (SBDL1, aqua, and SBDL2, yellow) which are located in the C-terminus. The amino acids (aa) comprising each domain are illustrated (PDB structure entry, 5HK).

FIGURE 2

Steroids regulate ion channels through Sigma-1 receptor actions. The scheme shows an overall view of ion channels regulated by the actions of steroids on Sig-1R. DHEA-S and PREG-S positively regulate (+) NMDAr trafficking and expression, whereas progesterone disrupts the association between NMDAr and Sig-1R and blocks the positive effects of the steroids on this channel’s regulation. Otherwise, an adverse effect (-) is produced on Na⁺ persistent currents by (DHEA-S). Indeed, hERG channels form protein complexes with Sig-1R, and this association is sensitive to cholesterol depletion. Also, L-type calcium channels are negatively regulated (-) by PREG-S in a strictly Sig-1R-dependent fashion. Finally, progesterone antagonizes Sig-1R which negatively regulates (-) the TRPV1 channel, producing protein instability of TRPV1 and reducing the amount of the channel in the plasma membrane. It is possible that progesterone has the same negative effects on hERG channel-expression.

FIGURE 3

Sigma-1 receptor and its endogenous ligands improve memory deficits. (A) The scheme represents the protein-complex between Sig-1R and NMDAr, which enhances the channel’s trafficking to the plasma membrane. (B) NMDAr antagonism produces deficits in memory and spatial work (upper panel). Sig-1R’s agonists such as DHEA-S, PREG-S, or SA4503, ameliorate memory impairments due to NMDAr antagonism (lower panel).

FIGURE 4

Progesterone attenuates pain-related behavior through disruption of the Sig-1R/TRPV1 complex. Sig-1R and TRPV1 channels are physically associated in the endoplasmic reticulum (ER), improving TRPV1 stability and resulting in suitable TRPV1 expression in the plasma membrane, where the channel transduces painful signals. Consequently, non-pregnant mice display pain behaviors in response to capsaicin paw-injection (left). However, in pregnant mice (right), when progesterone levels considerably increase, the formation of the complex between Sig-1R and the Binding immunoglobulin protein (BiP), is promoted. This maintains Sig-1R in a sequestered state and blocks its association with the TRPV1 channel, improving protein instability and avoiding degradation through the proteasomal pathway. Thus, TRPV1 protein levels in the plasma membrane decrease, leading to an increased pain threshold in response to capsaicin in pregnant mice.