Juxtaposition of the Steroid Binding Domain-like I and II Regions Constitutes a Ligand Binding Site in the σ-1 Receptor

Abstract

The receptors represent unique nonopioid and nonphencyclidine binding sites that are distinct from other known neurotransmitters or hormone receptors (4). Initially, Martin et al. (5) proposed the receptors as opioid receptors based on the psychomimetic effects of N-allyl-normetazocine (SKF-10047), which could not be explained by -or -opioid receptors (5). This hypothesis, however, was later corrected when the receptors were found to be insensitive to a common opioid receptor antagonist, naloxone (6 -8). Two well known subtypes of the receptor have been identified, the -1 receptor and the -2 receptor, which are distinguishable by their ligand binding properties and molecular weights (2, 9). They are ubiquitously expressed in different tissues, such as brain, adrenal gland, testis, ovary, spleen, lung, heart, blood leukocytes, and cancer cells (10 -15).Pharmacological studies have indicated that the -1 receptor is able to bind a wide range of compounds, including opiates (7,16,17), antipsychotics (18), antidepressants (18), antihistamines (16), phencyclidine-like compounds (19), ␤-adrenergic receptor ligands (7, 16), serotonergic compounds (16), cocaine and cocaine analogs (1, 20, 21), cholesterol (22), steroids (23-25), and neuropeptides (25), although intriguingly no known natural specific ligands have been discovered. In addition, -1 receptor knock-out mice are viable and fertile, showing no overt constitutive phenotype (26). However, the broad tissue distribution as well as the ability to bind different classes of ligands allows the -1 receptor to mediate various cellular events, such as modulation of voltage-gated K ϩ channels (27), calcium release (28), regulation of lipid compartmentalization on the endoplasmic reticulum (29), and "ligand-operated" chaperoning activity at "mitochondrion-associated endoplasmic reticulum membranes" (30). Regulation of cocaine effects (31, 32), neuroprotective effects (33), increase in extracellular acetylcholine levels (34), and inhibition of proliferative responses to mitogens (35) have also been ascribed to the -1 receptor. A role in psychostimulant actions has been proposed for the -1 receptor, based on methamphetamine binding (36).The -1 receptor has been cloned from different mammalian species, including guinea pigs (37), humans (38, 39), rats (40, 41), and mice (42), and shares about 90% identity and 95% similarity across these species. However, the -2 receptor has not been cloned yet. The cloned -1 receptor has 223 amino acids and shares 30% identity and 67% similarity with a yeast sterol C8-C7 isomerase (ERG2), which is involved in cholesterol synthesis (43). Interestingly, unlike the yeast sterol isomerase, the -1 receptor does not possess any sterol isomerase activity (37) and, in addition, shares no sequence homology with any known mammalian proteins, including the mammalian C8-C7 sterol isomerase. Hydrophobicity analysis indicates that the receptor and fungal sterol isomerases are topologically similar, each containing three hydrophobic regions. The first hydro...

A Review of the Human Sigma-1 Receptor Structure

“…3.1), and the importance of these regions in ligand binding was supported by derivatization studies using photoreactive analogs of cocaine [27] and fenpropimorph [28]. Chemical crosslinking and radio-ligand transfer between amino acids in SBDL1 and SBDL2 elegantly showed that the two regions are positioned close to each other in the folded receptor [28,29]. In a satisfying confirmation of those predictions, the S1R structures show that SBDL1 and SBDL2 envelope the bound ligands ( Fig.…”

“…125 I]IABM [29] and [ 125 I] IACoc [27], respectively, which have reactive groups on the primary hydrophobic feature, whereas H154 at the smaller end of the cupin barrel reacts with the photoprobe 4-NPPC12 [33], which has a reactive nitrophenol on the secondary hydrophobic feature.…”

Biochemical Pharmacology of the Sigma-1 Receptor

“…3B, i-iii). Several radioiodinated photoprobes have been developed in the Ruoho laboratory (Kahoun and Ruoho, 1992;Chen et al, 2007;Pal et al, 2007Pal et al, , 2008Fontanilla et al, 2008) (Fig. 3B, iv-ix).…”

Deconstruction of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety to separate P-glycoprotein (P-gp) activity from σ2 receptor affinity in mixed P-gp/σ2 receptor agents

“…1 H NMR, GC-MS and LC-MS data are the same reported below for both the enantiomers. 1 (10), 177 (100). The two compounds were obtained with a diastereomeric ratio > 99%.…”

“…The σ 1 protein has been isolated and cloned and it shows a unique structure with two transmembrane spanning segments [1]. With the main localization at the endoplasmic reticulum (ER) and mithocondria membranes, σ 1 subtype has been associated with chaperone function and with the modulation of the Ca 2+ levels within the cell [2,3].…”