Probing the Steroid Binding Domain-like I (SBDLI) of the Sigma-1 Receptor Binding Site Using N-Substituted Photoaffinity Labels

Fontanilla, Dominique; Hajipour, Abdol R.; Pal, Arindam; Chu, Uyen B.; Arbabian, Marty; Ruoho, Arnold E.

doi:10.1021/bi800564j

Cited by 36 publications

(51 citation statements)

References 34 publications

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“…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).…”

Section: Structural Features Of the S1r Ligand-binding Regionmentioning

confidence: 99%

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 S1r Ligand-binding Regionmentioning

confidence: 99%

Biochemical Pharmacology of the Sigma-1 Receptor

2015

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“…TIAM1-Rac1⅐GTP signaling is also important for dendrite branching. Thus, Tiam1-Rac1⅐GTP signaling is critical for the morphogenesis of dendritic spines especially in the later stages of neuronal maturation.Originally mistaken as a subtype of opioid receptors (11), the Sigma-1 receptor (Sig-1R) (12-15) is now known to be a nonopioid endoplasmic reticulum (ER)-resident protein (16)(17)(18)(19). Sig-1Rs are postulated to be involved in neuropsychiatric diseases including amnesia and addiction (13,20,21).…”

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confidence: 99%

“…Originally mistaken as a subtype of opioid receptors (11), the Sigma-1 receptor (Sig-1R) (12)(13)(14)(15) is now known to be a nonopioid endoplasmic reticulum (ER)-resident protein (16)(17)(18)(19). Sig-1Rs are postulated to be involved in neuropsychiatric diseases including amnesia and addiction (13,20,21).…”

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confidence: 99%

Sigma-1 receptors regulate hippocampal dendritic spine formation via a free radical-sensitive mechanism involving Rac1·GTP pathway

Tsai

Hayashi

Harvey

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

146

152

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Sigma-1 receptors (Sig-1Rs) are endoplasmic reticulum (ER)-resident proteins known to be involved in learning and memory. Dendritic spines in hippocampal neurons play important roles in neuroplasticity and learning and memory. This study tested the hypothesis that Sig-1Rs might regulate denritic spine formation in hippocampal neurons and examined potential mechanisms therein. In rat hippocampal primary neurons, the knockdown of Sig-1Rs by siRNAs causes a deficit in the formation of dendritic spines that is unrelated to ER Ca 2؉ signaling or apoptosis, but correlates with the mitochondrial permeability transition and cytochrome c release, followed by caspase-3 activation, Tiam1 cleavage, and a reduction in Rac1⅐GTP. Sig-1R-knockdown neurons contain higher levels of free radicals when compared to control neurons. The activation of superoxide dismutase or the application of the hydroxyl-free radical scavenger N-acetyl cysteine (NAC) to the Sig-1R-knockdown neurons rescues dendritic spines and mitochondria from the deficits caused by Sig-1R siRNA. Further, the caspase-3-resistant TIAM1 construct C1199DN, a stable guanine exchange factor able to constitutively activate Rac1 in the form of Rac1⅐GTP, also reverses the siRNA-induced dendritic spine deficits. In addition, constitutively active Rac1⅐GTP reverses this deficit. These results implicate Sig-1Rs as endogenous regulators of hippopcampal dendritic spine formation and suggest a free radicalsensitive ER-mitochondrion-Rac1⅐GTP pathway in the regulation of dendritic spine formation in the hippocampus. mitochondria ͉ ROS ͉ N-acetyl cyteine ͉ learning and memory ͉ caspase-3 D endritic spines in the CNS are important for many functions. Dendritic atrophy in the neocortical region is related to aging-induced amnesia, and its reversal improves memory retention (1). Similarly, the loss of dendritic spine-related synapses is currently a strong pathologic correlate of cognitive decline, and synaptic dysfunction is evident long before synapses and neurons are lost (2). On the other hand, exposure to drugs of abuse including cocaine, nicotine, or morphine produces persistent changes, usually in the form of increased dendritic spines and arborizations, in cells in brain regions involved in incentive motivation and reward (3). These persistent changes are thought to represent the neuronal reorganization that contributes to some of the persistent sequelae associated with drug use, including the establishment of motivational conditioning and learning (3).The morphology of dendritic spines and axons is determined by the dynamic cytoskeleton protein actin. Rho family small GTPases including Rho, Cdc42, and Rac1 regulate the dynamics of actin and are critical for neuronal polarization and morphogenesis (4-6). Rho proteins are regulated by guanine nucleotide exchange factors (GEFs). In early stages of neural morphogenesis, the activation of Cdc42 promotes the formation of filopodia, the long thin protrusions serving as primary precursors of axons and dendritic spines (7). However, Ra...

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“…Evidence suggests that structurally distinct -receptor ligands bind to different domains and that the binding sites may be allosterically coupled (56). 1 -Receptor ligands bind to residues in two steroid binding-like domains (38,39,47), as well as a third region (13). These three parts of the protein are thought to come together to form a single ligand binding site which includes parts of the protein implicated in steroid binding along with other parts not implicated in steroid binding.…”

Section: Discussionmentioning

confidence: 99%

Antagonist action of progesterone at σ-receptors in the modulation of voltage-gated sodium channels

Johannessen¹,

Fontanilla

Mavlyutov

et al. 2011

American Journal of Physiology-Cell Physiology

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σ-Receptors are integral membrane proteins that have been implicated in a number of biological functions, many of which involve the modulation of ion channels. A wide range of synthetic ligands activate σ-receptors, but endogenous σ-receptor ligands have proven elusive. One endogenous ligand, dimethyltryptamine (DMT), has been shown to act as a σ-receptor agonist. Progesterone and other steroids bind σ-receptors, but the functional consequences of these interactions are unclear. Here we investigated progesterone binding to σ(1)- and σ(2)-receptors and evaluated its effect on σ-receptor-mediated modulation of voltage-gated Na(+) channels. Progesterone binds both σ-receptor subtypes in liver membranes with comparable affinities and blocks photolabeling of both subtypes in human embryonic kidney 293 cells that stably express the human cardiac Na(+) channel Na(v)1.5. Patch-clamp recording in this cell line tested Na(+) current modulation by the σ-receptor ligands ditolylguanidine, PB28, (+)SKF10047, and DMT. Progesterone inhibited the action of these ligands to varying degrees, and some of these actions were reduced by σ(1)-receptor knockdown with small interfering RNA. Progesterone inhibition of channel modulation by drugs was consistent with stronger antagonism of σ(2)-receptors. By contrast, progesterone inhibition of channel modulation by DMT was consistent with stronger antagonism of σ(1)-receptors. Progesterone binding to σ-receptors blocks σ-receptor-mediated modulation of a voltage-gated ion channel, and this novel membrane action of progesterone may be relevant to changes in brain and cardiovascular function during endocrine transitions.

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Probing the Steroid Binding Domain-like I (SBDLI) of the Sigma-1 Receptor Binding Site Using N-Substituted Photoaffinity Labels

Cited by 36 publications

References 34 publications

Biochemical Pharmacology of the Sigma-1 Receptor

Biochemical Pharmacology of the Sigma-1 Receptor

Sigma-1 receptors regulate hippocampal dendritic spine formation via a free radical-sensitive mechanism involving Rac1·GTP pathway

Antagonist action of progesterone at σ-receptors in the modulation of voltage-gated sodium channels

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