Revisiting the sigma-1 receptor as a biological target to treat affective and cognitive disorders

Abstract

Depression and cognitive disorders are diseases with complex and not-fully understood etiology. Unfortunately, the COVID-19 pandemic dramatically increased the prevalence of both conditions. Since the current treatments are inadequate in many patients, there is a constant need for discovering new compounds, which will be more effective in ameliorating depressive symptoms and treating cognitive decline. Proteins attracting much attention as potential targets for drugs treating these conditions are sigma-1 receptors. Sigma-1 receptors are multi-functional proteins localized in endoplasmic reticulum membranes, which play a crucial role in cellular signal transduction by interacting with receptors, ion channels, lipids, and kinases. Changes in their functions and expression may lead to various diseases, including depression or memory impairments. Thus, sigma-1 receptor modulation might be useful in treating these central nervous system diseases. Importantly, two sigma-1 receptor ligands entered clinical trials, showing that this compound group possesses therapeutic potential. Therefore, based on preclinical studies, this review discusses whether the sigma-1 receptor could be a promising target for drugs treating affective and cognitive disorders.

Keywords: Animal models; Depression; Memory deficits; Sigma-1 receptors.

Fig. 1

A summary of the interaction of sigma-1 receptors with various proteins. After activating sigma-1 receptors, glucose-related protein 78/binding immunoglobulin protein (BiP) dissociates, and the sigma-1 receptor translocases into various cellular compartments, interacting with ion channels, G-protein coupled receptors, plasma proteins, mitochondria proteins, ER channels/proteins and nuclear proteins. BAF – barrier-to-autointegration factor, BiP – glucose-related protein 78/binding immunoglobulin protein, ELMOD – cell engulfment and motility domain, HDAC – histone deacetylase, HINT1 – histidine triad nucleotide-binding protein 1, IP₃Rs – inositol 1,4,5-trisphosphate receptors, IRE1α – inositol requiring kinase 1α, MAM – mitochondrial associated membranes, NMDA – N-methyl-D-aspartate, Orai1 – calcium release-activated calcium channel protein 1, PDGF – platelet-derived growth factor, StAR – steroidogenic acute regulatory protein, STIM1 – stromal interaction molecule 1,TrkB – tropomyosin receptor kinase B, VDAC 1,2 – voltage-dependent anion channel 1,2, XBP1s – X-box-binding proteins, Znf179 – zinc finger protein 179.

Fig. 2

The role of sigma-1 receptors in the antidepressant-like effect. The stimulation of sigma-1 receptors is necessary for an antidepressant-like effect.

Fig. 3

The role of sigma-1 receptors in memory and learning. The activation of sigma-1 receptors improves various types of memory in general. However, a few studies showed that the blockade of these receptors might also mediate the anti-amnesic effect.