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

Specific detection and deletion of the Sigma-1 receptor in neurons and glial cells for functional characterization in vivo

“…Activation or inactivation of S1Rs by exogenous ligands both showed therapeutic effects for numerous neurological and psychological disorders. However, endogenous ligands of the S1R still remain unclear, hindering the understanding of patho-as well as physiological roles of receptor in vivo (Sałaciak & Pytka, 2022; Schmidt & Kruse, 2019). Loss-of-function experiments would be an ideal strategy to investigate functions of S1R.…”

“…Previous studies using constitutive S1R KO mice suggest S1Rs are involved in the maintenance of cognitive, psychiatric, and motor functions, particularly with aging (Couly et al, 2022). Moreover, the S1R is considered as an enigmatic therapeutic target for various neurological disorders upon activation by its exogenous ligands including agonists and antagonists (Sałaciak & Pytka, 2022; Schmidt & Kruse, 2019). However, the contribution of cell-type-specific S1Rs to modulate the neural network activity under physiological and pathological conditions as well as upon activation is still not well understood, largely due to the lack of research tools inducing S1R deletion/overexpression in targeted cells in vivo .…”

Sigma-1 Receptors in Depression: Mechanism and Therapeutic Development

“…Many antidepressants that are currently marketed are known to act through the sigma-1 receptor pathway ( Hashimoto, 2009b ). Furthermore, some novel compounds based on the sigma-1 receptor confirmation are being synthesized and tested in depressive animal models, more information reviewed in ( Salaciak and Pytka, 2022 ). Although the exact therapeutic contribution of sigma-1 receptor binding remains to be unraveled, available data suggests that the anti-depressive efficacy is partly ascribed to sigma-1 receptor modulation.…”

“…Sigma receptors are divided into two subtypes (sigma-1 and sigma-2 receptors) and recently, the sigma-1 receptor, a type of chaperonin (28 kD), has attracted increasing attention for its broad spectrum of biological functions and as a potential target for drugs treating many medical conditions. Extensive research has revealed that sigma receptors play pivotal roles in the etiology of CNS diseases, including Alzheimer’s disease ( Maurice et al, 1998 ), Parkinson’s disease ( Francardo et al, 2014 ), schizophrenia ( Hashimoto, 2009a ; Takizawa et al, 2009 ), Huntington’s disease ( Bol'Shakova et al, 2017 ; Vetel et al, 2021 ), ischemic stroke ( Urfer et al, 2014 ), drug addiction ( Meunier et al, 2006 ), analgesia ( Davis, 2015 ; Shin et al, 2020 ), depression ( Kulkarni and Dhir, 2009 ; Salaciak and Pytka, 2022 ), anxiety ( Kulkarni and Dhir, 2009 ; Wang et al, 2019 ; Salaciak and Pytka, 2022 ) and cognitive disorders ( Salaciak and Pytka, 2022 ). Among them, mental disorders and cognitive deficits are currently the most widely studied areas.…”

“…This protein is identical in peripheral tissues and in the brain, and probably is similar in other tissues as well ( Rousseaux and Greene, 2016 ; Schmidt and Kruse, 2019 ). In the brain, sigma-1 receptors are distributed most abundantly in the hippocampus and hypothalamus, followed by the cerebellar area, the dorsal raphe nucleus (DRN) and the locus coeruleus (LC) ( Voronin et al, 2020 ; Salaciak and Pytka, 2022 ), and are mainly expressed in neurons and glial cells in the brain ( Nguyen et al, 2015 ). These various sites are related to cognition and motor, emotion and endocrine functions, and are also further involved in the pathophysiology of psychiatric disturbances of depression ( Voronin et al, 2020 ).…”