The Oligomeric States of the Purified Sigma-1 Receptor Are Stabilized by Ligands

Gromek, Katarzyna A.; Suchy, Fabian P.; Meddaugh, Hannah R.; Wrobel, Russell L.; LaPointe, Loren M.; Chu, Uyen B.; Primm, John G.; Ruoho, Arnold E.; Senes, Alessandro; Fox, Brian G.

doi:10.1074/jbc.m113.537993

Cited by 95 publications

(130 citation statements)

References 73 publications

(106 reference statements)

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“…Significant additional structural features of TM2 include a canonical membrane-imbedded GxxxG dimerization sequence (Overton et al, 2003) at positions 87-91, which is involved in oligomerization of the S1R (Gromek et al, 2014) (Fig. 3), and a single cysteine residue that occurs at position 94 in TM2.…”

Section: Structural Features Of the S1rmentioning

confidence: 99%

“…With the advent of effective methods to express the S1R in E. coli and purification of the S1R in native forms Gromek et al, 2013Gromek et al, , 2014, identification of the general location of certain ligand binding regions has been possible using various small molecule radiolabeled photoprobes. Selective cleavage of the specifically covalently photolabeled pure S1R has been achieved by EndoLys C at the lysine at position 142, followed in some cases, by additional cleavage with cyanogen bromide at methionines 90 and 170 followed by SDS-PAGE analyses.…”

Section: Structural Features Of the S1r Ligand-binding Regionmentioning

confidence: 99%

“…4) and site-directed mutagenesis data (Table 2), the shaded area broadly defines the ligand-binding site and perhaps a dimerization-dependent agonist binding interface between monomers. An ER retention sequence was determined by Hayashi and Su (2003), and the oligomerization sequence (GGMWG) of the sigma-1 receptor was based on studies published by Gromek et al (2014). Note: this model of the sigma-1 receptor is drawn from the perspective of the ER membrane; it is worth mentioning that the sigma-1 receptor will assume a reverse orientation on the plasma membrane where the N and C termini are extracellular.…”

Section: Structural Features Of the S1rmentioning

confidence: 99%

“…The S1R has been established as a therapeutic target for many neurodegenerative conditions in humans that involve various forms of cellular metabolic stress, including amyotrophic lateral sclerosis (Al-Saif et al, 2011;Mancuso et al, 2012;Mavlyutov et al, 2013Mavlyutov et al, , 2015Prause et al, 2013;Gromek et al, 2014;Fukunaga et al, 2015;Mishra et al, 2015), frontotemporal lobar dementia (Luty et al, 2010), Alzheimer disease (Feher et al, 2012;Yin et al, 2015), Parkinson disease (Mishina et al, 2005;Mori et al, 2012), retinal neurodegeneration (Smith et al, 2008;Mavlyutov et al, 2011;Shimazawa et al, 2015), addiction to drugs of abuse (Navarro et al, 2010;Nguyen et al, 2015), and psychiatric disorders (Tsai et al, 2014) (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

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Biochemical Pharmacology of the Sigma-1 Receptor

2015

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The sigma-1 receptor (S1R) is a 223 amino acid two transmembrane (TM) pass protein. It is a non-ATP-binding nonglycosylated ligand-regulated molecular chaperone of unknown three-dimensional structure. The S1R is resident to eukaryotic mitochondrial-associated endoplasmic reticulum and plasma membranes with broad functions that regulate cellular calcium homeostasis and reduce oxidative stress. Several multitasking functions of the S1R are underwritten by chaperone-mediated direct (and indirect) interactions with ion channels, G-protein coupled receptors and cell-signaling molecules involved in the regulation of cell growth. The S1R is a promising drug target for the treatment of several neurodegenerative diseases related to cellular stress. In vitro and in vivo functional and molecular characteristics of the S1R and its interactions with endogenous and synthetic small molecules have been discovered by the use of pharmacologic, biochemical, biophysical, and molecular biology approaches. The S1R exists in monomer, dimer, tetramer, hexamer/octamer, and higher oligomeric forms that may be important determinants in defining the pharmacology and mechanism(s) of action of the S1R. A canonical GXXXG in putative TM2 is important for S1R oligomerization. The ligand-binding regions of S1R have been identified and include portions of TM2 and the TM proximal regions of the C terminus. Some client protein chaperone functions and interactions with the cochaperone 78-kDa glucose-regulated protein (binding immunoglobulin protein) involve the C terminus. Based on its biochemical features and mechanisms of chaperone action the possibility that the S1R is a member of the small heat shock protein family is discussed.

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Section: Structural Features Of the S1rmentioning

confidence: 99%

Section: Structural Features Of the S1r Ligand-binding Regionmentioning

confidence: 99%

Section: Structural Features Of the S1rmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Biochemical Pharmacology of the Sigma-1 Receptor

2015

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“…S1; Skuza and Rogóz, 2006;Gromek et al, 2014) were used to investigate the acute effects of σ1Rs in CHO cells and HEK-σ1R cells. In CHO cells, σ1Rs are endogenously expressed (Hayashi and Su, 2007).…”

Section: Agonists and Antagonists Of σ1r Regulate Socementioning

confidence: 99%

Sigma1 receptors inhibit store-operated Ca²⁺ entry by attenuating coupling of STIM1 to Orai1

Srivats¹,

Balasuriya²,

Pasche³

et al. 2016

J Gen Physiol

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Sigma Receptor Binding Assays

Chu

Ruoho

2015

CP Pharmacology

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Sigma receptors belong to a class of small molecule-regulated, primarily endoplasmic reticulum (ER) membrane-associated receptors, of which there are two subtypes: the Sigma-1 receptor (S1R) and the Sigma-2 receptor (S2R). Both S1R and S2R bind to a number of drugs including antipsychotic, haloperidol, and the opioid analgesic, (+)-pentazocine. Sigma receptors are implicated in multiple disease pathologies associated with the nervous system including diseases affecting motor control such as Amyotrophic Lateral Sclerosis (ALS) and Alzeimher's disease. This unit describes methods for the pharmacological characterization of S1R and S2R using radioligand-binding assays. In the first section, radioligand saturation binding assay to determine receptor densities and competitive inhibition assays to characterize affinities of novel compounds are presented for S1R using the selective S1R ligand, [3H]-(+)-pentazocine. The second section describes radioligand saturation binding assay and competitive inhibition assays for the S2R using a non-selective S1R and S2R ligand, [3H]-1,3-di(2-tolyl)guanidine ([3H]-DTG).

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The Oligomeric States of the Purified Sigma-1 Receptor Are Stabilized by Ligands

Cited by 95 publications

References 73 publications

Biochemical Pharmacology of the Sigma-1 Receptor

Biochemical Pharmacology of the Sigma-1 Receptor

Sigma1 receptors inhibit store-operated Ca²⁺ entry by attenuating coupling of STIM1 to Orai1

Sigma Receptor Binding Assays

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The Oligomeric States of the Purified Sigma-1 Receptor Are Stabilized by Ligands

Cited by 95 publications

References 73 publications

Biochemical Pharmacology of the Sigma-1 Receptor

Biochemical Pharmacology of the Sigma-1 Receptor

Sigma1 receptors inhibit store-operated Ca2+ entry by attenuating coupling of STIM1 to Orai1

Sigma Receptor Binding Assays

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Sigma1 receptors inhibit store-operated Ca²⁺ entry by attenuating coupling of STIM1 to Orai1