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Biochemical Pharmacology of the Sigma-1 Receptor

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Biochemical Pharmacology of the Sigma-1 Receptor 1521-0111/89/1/142–153$25.00 http://dx.doi.org/10.1124/mol.115.101170 MOLECULAR PHARMACOLOGY Mol Pharmacol 89:142–153, January 2016 Copyright ª 2015 by The American Society for Pharmacology and Experimental Therapeutics MINIREVIEW Biochemical Pharmacology of the Sigma-1 Receptor Uyen B. Chu and Arnold E. Ruoho Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin Received July 31, 2015; accepted November 6, 2015 Downloaded from ABSTRACT The sigma-1 receptor (S1R) is a 223 amino acid two transmem- been discovered by the use of pharmacologic, biochemical, brane (TM) pass protein. It is a non-ATP-binding nonglycosylated biophysical, and molecular biology approaches. The S1R exists ligand-regulated molecular chaperone of unknown three-dimensional in monomer, dimer, tetramer, hexamer/octamer, and higher structure. The S1R is resident to eukaryotic mitochondrial-associated oligomeric forms that may be important determinants in defining endoplasmic reticulum and plasma membranes with broad functions the pharmacology and mechanism(s) of action of the S1R. A molpharm.aspetjournals.org that regulate cellular calcium homeostasis and reduce oxidative canonical GXXXG in putative TM2 is important for S1R oligomer- stress. Several multitasking functions of the S1R are underwritten ization. The ligand-binding regions of S1R have been identified by chaperone-mediated direct (and indirect) interactions with and include portions of TM2 and the TM proximal regions of the C ion channels, G-protein coupled receptors and cell-signaling terminus. Some client protein chaperone functions and interac- molecules involved in the regulation of cell growth. The S1R is a tions with the cochaperone 78-kDa glucose-regulated protein promising drug target for the treatment of several neurodegen- (binding immunoglobulin protein) involve the C terminus. Based erative diseases related to cellular stress. In vitro and in vivo on its biochemical features and mechanisms of chaperone action functional and molecular characteristics of the S1R and its the possibility that the S1R is a member of the small heat shock interactions with endogenous and synthetic small molecules have protein family is discussed. at ASPET Journals on October 1, 2021 Introduction amino acid protein with 90% sequence conservation in many mammalian species. The S1R is located in eukaryotic This minireview summarizes current aspects of the molec- mitochondrial-associated endoplasmic reticulum membranes ular pharmacology and biochemistry of the sigma-1 receptor (Hayashi and Su, 2007) and in some plasma membrane com- (S1R). The remarkable history of the S1R extends from the partments (Mavlyutov and Ruoho, 2007; Mavlyutov et al., 2010, late 1970s and early 1980s (Martin et al., 1976; Su, 1981, 1988; 2012). Notable molecular features of the S1R include 1) two Tam, 1983; Vaupel, 1983; Tam and Cook, 1984; Largent et al., putative transmembrane sequences, which predicts that both 1986, 1987; Sircar et al., 1986a; Weber et al., 1986; Itzhak, the N and C termini are located on the same side of the mem- 1987; McLean and Weber, 1988; Sharkey et al., 1988; Bowen brane, 2) the presence of several splice variants (Ganapathy et al., 1989; de Costa et al., 1989; Hellewell and Bowen, 1990) et al., 1999), and 3) endogenous and synthetic ligand regulation to the present day. The reader is directed to the earlier of its chaperone functions (Hayashi and Su, 2007). publications and reviews that outline the original pharmaco- The gene that encodes for the human S1R is located on logic identification of this important receptor (Martin, 1983; chromosome 9 band p13 and contains four exons and three Su and Hayashi, 2003; Glennon, 2005). introns. The S1R shares 60% amino acid identity to a yeast The guinea pig S1R was originally purified and cloned by sterol isomerase, ERG2, however, the mammalian S1R does Hanner et al. (1996), who found that the S1R is a unique 223 not possess sterol isomerase activity, nor can it rescue the growth of sterol isomerase-deficient yeast (Moebius et al., 1996, Supported by a University of Wisconsin School of Medicine and Public – Health grant (to A.E.R.). 1997). The S1R is a ligand-regulated non ATP-binding mem- dx.doi.org/10.1124/mol.115.101170. brane bound chaperone protein (Hayashi and Su, 2007). In its ABBREVIATIONS: BD-1047, Nʹ-[2-(3,4-dichlorophenyl)ethyl]-N,N,Nʹ-trimethylethane-1,2-diamine; BD-1063, N-[2-(3,4-dichlorophenyl) ethyl]-4- methylpiperazine dihydrochloride; BiP, binding immunoglobulin protein; cdk5, cyclin-dependent kinase 5; ER, endoplasmic reticulum; GPCR, G-protein coupled receptor; GRP78, 78-kDa glucose-regulated protein; hERG, human ether-à-go-go; HSP, heat shock protein; [125I]-IACoc, [125I]-iodoazidococaine; [125I]-IABM, S-[[4-(4-amino-3-[125I] iodobenzoyl phenyl] methyl] ester; [125I]-IAC44, N-propyl-N-(4-azido-3-iodophenylethyl)- 125 125 3-(4-fluorophenyl) propylamine; ( I)-IAF, ( I)-iodoazidofenpropimorph; IP3, inositol triphosphate; LDAO, lauryl dimethylamine N-oxide; NE-100, N, N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride; 4-NPPC12, N-3-(4-nitrophenylpropyl) dodecan-1-amine; PRE-084, 2-(4-morpholinethyl) 1-phenylcyclohexane-1-carboxylate hydrochloride; SKF10047, [2S-(2a,6a,11R*]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)- 2,6-methano-3-benzazocin-8-ol; S1R, sigma-1 receptor; SBLD, steroid-binding-like domain; sHSP, small heat shock protein; TM, transmembrane. 142 Biochemical Pharmacology of the Sigma-1 Receptor 143 multitasking functions, the S1R has been demonstrated to N-aralkyl substituent. After analysis of many structure-activity physically interact with client proteins in a functional manner studies compiled from at least 2 to 3 decades of intense activity including ion channels such as inositol triphosphate (IP3) involving small molecule S1R selective syntheses, it has been receptors (Hayashi and Su, 2001; Wu and Bowen, 2008), generally agreed that this primary hydrophobic component is voltage-gated potassium (Aydar et al., 2002), sodium (Balasuriya optimally situated at approximately five carbons (6–10 Å) from et al., 2012), and calcium channels (Tchedre et al., 2008), the nitrogen. A secondary hydrophobic group can be located closer calcium-activated chloride channels (Zhang and Cuevas, to the obligate nitrogen (2.5–4 Å) than the primary hydrophobic 2002), and N-methyl-D-aspartate receptors (Sircar et al., 1986b; group. Additionally, Ruoho et al. (2012) have shown that para- Monnet et al., 1990; Balasuriya et al., 2013; Pabba et al., 2014). nitro or para-azido electron-withdrawing groups on the phenyl Specific interactions of the S1R with several types of G-protein ring of molecules such as cocaine (Chen et al., 2007) greatly coupled receptors (GPCRs) (Kim et al., 2010). Navarro et al. enhance the specific S1R-binding affinity (discussed later). (2010) have also been reported. The S1R directly and indirectly Similarly the binding of a series of N-3-(4-nitrophenyl) propyl- modulates neuronal mitochondrial Rac-1 GTPase (Tsai et al., Nʹ-alkylamines to the pure S1R in which the Nʹ-alkyl chains 2009; Natsvlishvili et al., 2015), which is involved in dendritic varied from propyl to octadecyl showed a similar increase in spine formation. S1R reduces tau phosphorylation (Tsai et al., affinity compared with their parent N-phenylalkyl amines 2015) via indirect regulation of cyclin-dependent kinase 5 (cdk5) (Ruoho et al., 2012). and thus protects neuronal axon elongation. (Fig. 1). A minimal pharmacophore for S1R binding based on a Downloaded from The S1R has been established as a therapeutic target for phenylalkylamine platform (Maeda et al., 2002; Fontanilla many neurodegenerative conditions in humans that involve et al., 2009) has led to the identification of a plethora of com- various forms of cellular metabolic stress, including amyotro- pounds with reasonable (and in some cases exceptional) S1R- phic lateral sclerosis (Al-Saif et al., 2011; Mancuso et al., 2012; binding affinity as either agonists or antagonists (selected Mavlyutov et al., 2013, 2015; Prause et al., 2013; Gromek et al., compounds are shown in Table 1). Upon examination of 2014; Fukunaga et al., 2015; Mishra et al., 2015), frontotempo- the benzomorphans, such as pentazocine and SKF10047 molpharm.aspetjournals.org ral lobar dementia (Luty et al., 2010), Alzheimer disease (Feher ([2S-(2a,6a,11R*]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2- et al., 2012; Yin et al., 2015), Parkinson disease (Mishina et al., propenyl)-2,6-methano-3-benzazocin-8-ol), an important fea- 2005; Mori et al., 2012), retinal neurodegeneration (Smith et al., ture involving the stereospecificity of binding to the S1R is 2008; Mavlyutov et al., 2011; Shimazawa et al., 2015), addiction emphasized; that is, the dextrorotatory forms bind to the S1R to drugs of abuse (Navarro et al., 2010; Nguyen et al., 2015), and with significantly higher affinity than the levorotatory forms. psychiatric disorders (Tsai et al., 2014) (Fig. 1). Given this generally promiscuous pharmacophore, several small molecules that are able to bind to other drug targets also interact Commonly Used Agonists/Antagonists for the with the S1R, such as fenpropimorph (antifungal), haloperidol (antipsychotic), chlorpheniramine (antihistamine), N,Nʹ di- S1R methyl tryptamine (DMT) and methamphetamine (psychosti- at ASPET Journals on October 1, 2021 Glennon (2005) proposed that the pharmacophore for small mulants), fluvoxamine (antidepressant), and verapamil (calcium
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