The sigma receptor: evolution of the concept in neuropsychopharmacology - PubMed (original) (raw)

The sigma receptor: evolution of the concept in neuropsychopharmacology

T Hayashi et al. Curr Neuropharmacol. 2005 Oct.

Abstract

Although originally proposed as a subtype of opioid receptors, the sigma receptor is now confirmed to be a non-opioid receptor that binds diverse classes of psychotropic drugs. Sigma receptors are subdivided into two subtypes, sigma-1 and sigma-2. The sigma-1 receptor is a 25-kDa protein possessing one putative transmembrane domain and an endoplasmic reticulum retention signal. Sigma-1 receptors are highly expressed in deeper laminae of the cortex, olfactory bulb, nuclei of mesencephalon, hypothalamus, and Purkinje cells in the brain. Sigma-1 receptors are predominantly localized at the endoplasmic reticulum of both neurons and oligodendrocytes. From behavioral studies, sigma-1 receptors were shown to be involved in higher-ordered brain functions including memory and drug dependence. The actions mediated by sigma-1 receptors at the cellular level can be considered either as acute or chronic. The acute actions include the modulation of ion channels (i.e., K+ channel, NMDA receptors, IP3 receptors) and the sigma-1 receptor translocation. Chronic actions of sigma-1 receptors are basically considered to be the result of an up- or down regulation of the sigma-1 receptor itself. For example, the upregulation of sigma-1 receptors per se, even without exogenous ligands, promotes cellular differentiation and reconstitution of lipid microdomains (lipid rafts) in cultured cells. These findings together suggest that sigma-1 receptors might possess a constitutive biological activity, and that sigma-1 receptor ligands might merely work as modulators of the innate activity of this protein. Recent in vitro and in vitro studies strongly point to the possibility that sigma-1 receptors participate in membrane remodeling and cellular differentiation in the nervous system.

Keywords: IP3 receptor; Sigma receptor; differentiation; drug dependence; lipid rafts; oligodendrocyte; potassium channel; sigma-1 receptor.

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Figures

Fig. (1)

Fig. (1)

Protein structure of the sigma-1 receptor.

Fig. (2)

Fig. (2)

Brain distribution of sigma-1 receptors. Sigma-1 receptors in adult rat brains were visualized by immunofluorescence using anti-sigma-1 receptor antibodies and Alexa480-conjugated secondary antibodies. Images were captured by fluorescence confocal microscopy. (A) Olfactory bulb, (B-C) parietal cortex. Arrows indicate dendrites. (D) Subventricular zone. LV: lateral ventricle. (E-F) Hippocampus CA3, (G) corpus callosum, (H-I) cerebellum. Scale bars in A, B, D, and H are 100 ;Cm, others are 20 ;m.

Fig. (3)

Fig. (3)

Cellular distribution of sigma-1 receptors. Sigma-1 receptors are detected by immunofluorescence as described in Fig. (2). (a) Cellular distribution of sigma-1 receptors in a NG-108 cell. Sigma-1 receptors are highly clustered and localized at the perinuclear region in NG-108 cells. (b) Cellular distribution of sigma-1 receptors in a mature oligodendrocyte from the rat brain. Z-dimensional images are captured along horizontal and vertical white lines, respectively. Orthogonal sections indicate that clusters of sigma-1 receptors are located in cytoplasm of the myelin sheet. Scale bars=10 ;m.

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