Sigma-1 Receptor Plays a Negative Modulation on N-type Calcium Channel

Abstract

The sigma-1 receptor is a 223 amino acids molecular chaperone with a single transmembrane domain. It is resident to eukaryotic mitochondrial-associated endoplasmic reticulum and plasma membranes. By chaperone-mediated interactions with ion channels, G-protein coupled receptors and cell-signaling molecules, the sigma-1 receptor performs broad physiological and pharmacological functions. Despite sigma-1 receptors have been confirmed to regulate various types of ion channels, the relationship between the sigma-1 receptor and N-type Ca2+ channel is still unclear. Considering both sigma-1 receptors and N-type Ca2+ channels are involved in intracellular calcium homeostasis and neurotransmission, we undertake studies to explore the possible interaction between these two proteins. In the experiment, we confirmed the expression of the sigma-1 receptors and the N-type calcium channels in the cholinergic interneurons (ChIs) in rat striatum by using single-cell reverse transcription-polymerase chain reaction (scRT-PCR) and immunofluorescence staining. N-type Ca2+ currents recorded from ChIs in the brain slice of rat striatum was depressed when sigma-1 receptor agonists (SKF-10047 and Pre-084) were administrated. The inhibition was completely abolished by sigma-1 receptor antagonist (BD-1063). Co-expression of the sigma-1 receptors and the N-type calcium channels in Xenopus oocytes presented a decrease of N-type Ca2+ current amplitude with an increase of sigma-1 receptor expression. SKF-10047 could further depress N-type Ca2+ currents recorded from oocytes. The fluorescence resonance energy transfer (FRET) assays and co-immunoprecipitation (Co-IP) demonstrated that sigma-1 receptors and N-type Ca2+ channels formed a protein complex when they were co-expressed in HEK-293T (Human Embryonic Kidney -293T) cells. Our results revealed that the sigma-1 receptors played a negative modulation on N-type Ca2+ channels. The mechanism for the inhibition of sigma-1 receptors on N-type Ca2+ channels probably involved a chaperone-mediated direct interaction and agonist-induced conformational changes in the receptor-channel complexes on the cell surface.

Sigma‐1 receptor activation‐induced glycolytic ATP production and endothelial barrier enhancement

“…To test the impact of σ1 activation on endothelial barrier function, we performed a concentration‐response study with the highly selective σ1 agonist, PRE‐084, at concentrations of 1, 5, 10, 50, 100, 150, and 200 μM, based on previously reported data 6,40‐42 . The results show a concentration‐dependent increase in barrier enhancement (Figure 1A,B).…”

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

“…FRET and coimmunoprecipitation experiments demonstrated that N-type channels and Sig-1R form protein-complexes when these proteins are expressed in HEK293 cells. The authors of this study proposed that Sig-1R agonists produce a conformational change in these protein complexes that negatively regulates N-type channels (Zhang et al, 2017).…”

The Roles of Intracellular Chaperone Proteins, Sigma Receptors, in Parkinson’s Disease (PD) and Major Depressive Disorder (MDD)

“…The Sigma-1 receptor could enhance or inhibit Ca 2+ channel activity through either direct or indirect actions (Kourrich et al., 2012). To date, only few studies have shown the direct action of Sigma-1 receptor on Ca 2+ channels in the CNS (Mueller et al., 2013; Zhang et al., 2017). In cultured retinal ganglion cells, the activation of Sigma-1 receptor by SKF10047 inhibited Ca 2+ currents, and this effect was abolished by Sigma-1 receptor antagonist BD 1047.…”

“…In addition, the association between the Sigma-1 receptor and Ca 2+ channel was shown by Co-IP experiments (Mueller et al., 2013). N-type Ca 2+ currents from cholinergic interneurons in rat striatum were also reduced by Sigma-1 receptor agonists (SKF-10047 and Pre-084) (Zhang et al., 2017), this inhibition was prevented by Sigma-1 receptor antagonist BD 1063. Sigma-1 receptors and N-type Ca 2+ channels bind together, which is demonstrated by FRET assays and Co-IP (Zhang et al., 2017).…”