kinesin 5 Overexpression of the sigma receptor also leads to

Overexpression of the sigma-1 receptor also leads to its increased translocation to the plasma membrane [17]. It was demonstrated in a mouse model [18] that chronic alcohol consumption causes increased expression (and therefore, possibly, translocation to the plasma membrane) of the sigma-1 receptor in the brain. At the same time, a recent study by Yao et al. [19] has revealed that cocaine causes the sigma-1 receptor to translocate from the ER to the lipid rafts of the plasma membrane, where chemokines CCL2 are induced in microglia via Src-kinase activation. It is also shown that overexpression of the sigma-1 receptor in cortical neurons increases the binding of the tyrosine kinase receptor B and phospholipase C [20]. After translocating to the plasma membrane, the sigma-1 receptor interacts with various ion channels, receptors and kinases [21]. In fact, it was demonstrated using the patch-clamp on pituitary gland kinesin 5 that pentazocine, which is a sigma-1 receptor agonist, inhibits the outward current of potassium ions (K+), and this phenomenon can be reversed by the sigma-1 receptor antagonist NE-100 [22]. In addition to direct physical interaction and regulation of the activity of voltage-gated K+ channels in mouse nerve terminals of the posterior lobe of the pituitary gland [23], the sigma-1 receptor regulates the activity of the K+ channel in rat hippocampal slices, intracardiac neurons and cancer cells [24]. The sigma-1 receptor ligands modulate several types of presynaptic Са2+ channels in rat sympathetic and parasympathetic neurons [25]. The sigma-1 receptor also modulates the NMDA receptor activity [26] and affects synaptic plasticity through the small-conductance Са2+-activated K+ channels [27]. The sigma-1 receptor has been shown to modulate cardiac voltage-gated Na+ channels in HEK293 and COS- cells, as well as in neonatal mouse cardiomyocytes [28]. SKF-10047, a sigma-1 receptor agonist, inhibits calcium ion currents in cultured retinal ganglion cells. Direct association between the sigma-1 receptor and the L-type Ca2+-channel was performed using immunoprecipitation [29]. There is also data indicating that the sigma-1 receptor regulates neurotransmitter release in dopaminergic, serotonergic and cholinergic transmission, and is involved in cell differentiation, cellular responses to inflammation, and in pathogenesis of extrapyramidal disorders [21]. Interestingly, the sigma-1 receptor was detected in the extracellular space of NG-108 cells exposed to cocaine, indicating that the receptor possibly acts as a chaperone in the extracellular space [7].
The structure of the sigma-1 receptor The sigma-1 receptor is an integral membrane receptor, and it is predominantly localized in the ER membranes associated with mitochondria [16]. Even though the detailed atomic structure of the receptor has not yet been determined, a number of studies have been focused on establishing the protein topology and on mapping its active site. Initially, the sigma-1 receptor has been characterized as a type I transmembrane protein with a single transmembrane domain [30]. Currently, a fairly large number of experimental data indicates that there are two alpha-helical transmembrane domains. This data was obtained via bioinformatic analysis, molecular simulation, epitope mapping techniques, limited proteolysis, and NMR spectroscopy. The number and localization of transmembrane domains are different and depend on the specific algorithm chosen for predicting hydrophobic domains based on the amino acid sequence (Fig. 1) [31–37]. Most algorithms indicate the presence of two or three hydrophobic regions (see. Fig. 1). The first two domains have been identified as highly ordered transmembrane alpha-helices (TM1, TM2). The second transmembrane helix has amphipathic properties [38]. Amino acids 91–109 and 176–194 contain highly conserved sequences homologous to the yeast and fungal sterol C8–C7 isomerase. Due to their homology, these sequences were named steroid-binding domain-like I and II (SBDLI and SBDLII) (Fig. 2a) [39].