Contact
Triad Technology Center333 Cassell Drive
Room 3304
Baltimore, MD 21224
Phone: 667-312-5292
Email: TSU@intra.nida.nih.gov
Education
Post-doctoral Training - Stanford University School of Medicine, Dept. of Pharmacology, mentor: Professor Avram Goldstein
Ph.D. - Biochemistry, School of Medicine, State University of New York at Buffalo
B.S. - National Taiwan University, Taipei, Taiwan
Research Interests
The Cellular Pathobiology section examines the cellular and molecular biological mechanisms whereby addictive processes might be formed. Specifically, the laboratory studies how psychostimulants might utilize signaling molecules at the protein synthesizing organelle the endoplasmic reticulum (ER) and the cellular powerhouse mitochondria (MITO) to alter neuronal infrastructures and morphometries that ultimately favor the formation of addictive processes. The laboratory uses three levels of living systems to address and test relevant hypotheses: cell lines, primary neuronal systems, and rodents. The rodent studies are from collaborative efforts with other sections at the institute. The techniques employed in the laboratory include molecular biological manipulation of proteins, FRET, Ca2+ dynamics assays and imaging, protein trafficking studies with fluorescence imaging and pulse-chase experiments, neuronal morphometric studies with confocal microscope, and bio-signal engineerings. The laboratory currently focuses on a protein called the sigma-1 receptor (Sig-1R) that resides specifically at the ER-MITO interface of cells and is implicated in alterations of neuronal structures and in the addiction of cocaine and methamphetamine. Ongoing projects include: (1) mechanisms of action of Sig-1Rs as ligand-regulated molecular chaperones in bioenergenetics and cell survival; (2) roles of Sig-1Rs in lipid raft formation; (3) metabolic engineering on intracellular signaling pathways; (4) roles of Sig-1Rs in the regulation of ER stress; (5) Sig-1R regulation of dendritic spine and axon formations in the brain; and (6) roles of Sig-1Rs in the self-administration of cocaine and methamphetamine in the rat.
Publications
Selected Publications
Lin, Chun-Yu; Wu, Hsuan-Cheng; Fu, Ru-Huei; Weng, Eddie Feng-Ju; Hsieh, Wen-Chi; Su, Tsung-Ping; Wu, Hsiang-En; Wang, Shao-Ming Sigma-1R-Pom121 axis preserves nuclear transport and integrity in poly-PR-induced C9orf72 ALS Journal Article In: Neurobiol Dis, vol. 212, pp. 106992, 2025, ISSN: 1095-953X. Lin, Chun-Yu; Wu, Hsiang-En; Weng, Eddie Feng-Ju; Wu, Hsuan-Cheng; Su, Tsung-Ping; Wang, Shao-Ming Fluvoxamine Exerts Sigma-1R to Rescue Autophagy via Pom121-Mediated Nucleocytoplasmic Transport of TFEB Journal Article In: Mol Neurobiol, vol. 61, no. 8, pp. 5282–5294, 2024, ISSN: 1559-1182. Couly, Simon; Yasui, Yuko; Foncham, Semnyonga; Grammatikakis, Ioannis; Lal, Ashish; Shi, Lei; Su, Tsung-Ping Benzomorphan and non-benzomorphan agonists differentially alter sigma-1 receptor quaternary structure, as does types of cellular stress Journal Article In: Cell Mol Life Sci, vol. 81, no. 1, pp. 14, 2024, ISSN: 1420-9071. Wang, Shao-Ming; Wu, Hsiang-En; Yasui, Yuko; Geva, Michal; Hayden, Michael; Maurice, Tangui; Cozzolino, Mauro; Su, Tsung-Ping Nucleoporin POM121 signals TFEB-mediated autophagy via activation of SIGMAR1/sigma-1 receptor chaperone by pridopidine Journal Article In: Autophagy, vol. 19, no. 1, pp. 126–151, 2023, ISSN: 1554-8635. Crouzier, Lucie; Danese, Alberto; Yasui, Yuko; Richard, Elodie M; Liévens, Jean-Charles; Patergnani, Simone; Couly, Simon; Diez, Camille; Denus, Morgane; Cubedo, Nicolas; Rossel, Mireille; Thiry, Marc; Su, Tsung-Ping; Pinton, Paolo; Maurice, Tangui; Delprat, Benjamin Activation of the sigma-1 receptor chaperone alleviates symptoms of Wolfram syndrome in preclinical models Journal Article In: Sci Transl Med, vol. 14, no. 631, pp. eabh3763, 2022, ISSN: 1946-6242. Lee, Pin-Tse; Liévens, Jean-Charles; Wang, Shao-Ming; Chuang, Jian-Ying; Khalil, Bilal; Wu, Hsiang-en; Chang, Wen-Chang; Maurice, Tangui; Su, Tsung-Ping Sigma-1 receptor chaperones rescue nucleocytoplasmic transport deficit seen in cellular and Drosophila ALS/FTD models Journal Article In: Nature Communications, vol. 11, no. 1, pp. 5580, 2020, ISBN: 2041-1723. Su, Tsung-Ping; Su, Tzu-Chieh; Nakamura, Yoki; Tsai, Shang-Yi The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems. Journal Article In: Trends Pharmacol Sci, vol. 37, no. 4, pp. 262–278, 2016, ISSN: 1873-3735 (Electronic); 0165-6147 (Linking). Tsai, Shang-Yi A; Chuang, Jian-Ying; Tsai, Meng-Shan; Wang, Xiao-Fei; Xi, Zheng-Xiong; Hung, Jan-Jong; Chang, Wen-Chang; Bonci, Antonello; Su, Tsung-Ping Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope. Journal Article In: Proc Natl Acad Sci U S A, vol. 112, no. 47, pp. E6562-70, 2015, ISSN: 1091-6490 (Electronic); 0027-8424 (Linking). Tsai, Shang-Yi A; Pokrass, Michael J; Klauer, Neal R; Nohara, Hiroshi; Su, Tsung-Ping Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid. Journal Article In: Proc Natl Acad Sci U S A, vol. 112, no. 21, pp. 6742–6747, 2015, ISSN: 1091-6490 (Electronic); 0027-8424 (Linking). Kourrich, Said; Hayashi, Teruo; Chuang, Jian-Ying; Tsai, Shang-Yi; Su, Tsung-Ping; Bonci, Antonello Dynamic interaction between sigma-1 receptor and Kv1.2 shapes neuronal and behavioral responses to cocaine. Journal Article In: Cell, vol. 152, no. 1-2, pp. 236–247, 2013, ISSN: 1097-4172 (Electronic); 0092-8674 (Linking). Tsai, Shang-Yi; Hayashi, Teruo; Harvey, Brandon K; Wang, Yun; Wu, Wells W; Shen, Rong-Fong; Zhang, Yongqing; Becker, Kevin G; Hoffer, Barry J; Su, Tsung-Ping Sigma-1 receptors regulate hippocampal dendritic spine formation via a free radical-sensitive mechanism involving Rac1xGTP pathway. Journal Article In: Proc Natl Acad Sci U S A, vol. 106, no. 52, pp. 22468–22473, 2009, ISSN: 1091-6490 (Electronic); 0027-8424 (Linking). Hayashi, Teruo; Su, Tsung-Ping Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Journal Article In: Cell, vol. 131, no. 3, pp. 596–610, 2007, ISSN: 0092-8674 (Print); 0092-8674 (Linking). Hayashi, Teruo; Su, Tsung-Ping Sigma-1 receptors at galactosylceramide-enriched lipid microdomains regulate oligodendrocyte differentiation. Journal Article In: Proc Natl Acad Sci U S A, vol. 101, no. 41, pp. 14949–14954, 2004, ISSN: 0027-8424 (Print); 0027-8424 (Linking). Hayashi, T; Su, T P Regulating ankyrin dynamics: Roles of sigma-1 receptors. Journal Article In: Proc Natl Acad Sci U S A, vol. 98, no. 2, pp. 491–496, 2001, ISSN: 0027-8424 (Print); 0027-8424 (Linking). Su, T P; London, E D; Jaffe, J H Steroid binding at sigma receptors suggests a link between endocrine, nervous, and immune systems. Journal Article In: Science, vol. 240, no. 4849, pp. 219–221, 1988, ISSN: 0036-8075 (Print); 0036-8075 (Linking).2025
@article{pmid40480424,
title = {Sigma-1R-Pom121 axis preserves nuclear transport and integrity in poly-PR-induced C9orf72 ALS},
author = {Chun-Yu Lin and Hsuan-Cheng Wu and Ru-Huei Fu and Eddie Feng-Ju Weng and Wen-Chi Hsieh and Tsung-Ping Su and Hsiang-En Wu and Shao-Ming Wang},
url = {https://pubmed.ncbi.nlm.nih.gov/40480424/},
doi = {10.1016/j.nbd.2025.106992},
issn = {1095-953X},
year = {2025},
date = {2025-08-01},
urldate = {2025-08-01},
journal = {Neurobiol Dis},
volume = {212},
pages = {106992},
abstract = {Nucleocytoplasmic transport disruption contributes to the pathogenesis of C9orf72-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Among the dipeptide repeat proteins translated from G4C2-repeat RNA, poly-PR is particularly toxic, compromising nuclear envelope integrity and transport. Here, we revealed that poly-PR reduced expression of the nucleoporin Pom121 in NSC-34 cells and in an AAV-mediated poly-PR mouse model, resulting in cytoplasmic mislocalization of the neuroprotective transcription factor ATF3 and nuclear envelope damage. Pom121 overexpression restored nuclear ATF3 localization and alleviated poly-PR-induced toxicity. We further identified Sigma-1 receptor (Sigma-1R) as a stabilizer of Pom121 that preserved nuclear integrity and ATF3 function under oxidative stress. Overexpression of Sigma-1R, Pom121, or ATF3 rescued poly-PR-induced cytotoxicity. Our findings defined a protective Sigma-1R/Pom121/ATF3 axis and suggested this pathway as a therapeutic target in C9orf72-linked ALS.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2024
@article{pmid38180612,
title = {Fluvoxamine Exerts Sigma-1R to Rescue Autophagy via Pom121-Mediated Nucleocytoplasmic Transport of TFEB},
author = {Chun-Yu Lin and Hsiang-En Wu and Eddie Feng-Ju Weng and Hsuan-Cheng Wu and Tsung-Ping Su and Shao-Ming Wang},
url = {https://pubmed.ncbi.nlm.nih.gov/38180612/},
doi = {10.1007/s12035-023-03885-9},
issn = {1559-1182},
year = {2024},
date = {2024-08-01},
urldate = {2024-08-01},
journal = {Mol Neurobiol},
volume = {61},
number = {8},
pages = {5282--5294},
abstract = {Expansion of the GGGGCC-RNA repeat is a known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which currently have no cure. Recent studies have indicated the activation of Sigma-1 receptor plays an important role in providing neuroprotection, especially in ALS and Alzheimer's disease. Nevertheless, the mechanisms underlying Sigma-1R activation and its effect on (GC)n-RNA-induced cell death remain unclear. In this study, we demonstrated that fluvoxamine is a Sigma-1R agonist that can increase chaperone activity and stabilize the protein expression of Pom121 in (GC)-RNA-expressing NSC34 cells, leading to increased colocalization at the nuclear envelope. Interestingly, fluvoxamine treatment increased Pom121 protein expression without affecting transcription. In C9orf72-ALS, the nuclear translocation of TFEB autophagy factor decreased owing to nucleocytoplasmic transport defects. Our results showed that pretreatment of NSC34 cells with fluvoxamine promoted the shuttling of TFEB into the nucleus and elevated the expression of LC3-II compared to the overexpression of (GC)-RNA alone. Additionally, even when used alone, fluvoxamine increases Pom121 expression and TFEB translocation. To summarize, fluvoxamine may act as a promising repurposed medicine for patients with C9orf72-ALS, as it stabilizes the nucleoporin Pom121 and promotes the translocation of TFEB in (GC)-RNA-expressing NSC34 cells.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{pmid38191696,
title = {Benzomorphan and non-benzomorphan agonists differentially alter sigma-1 receptor quaternary structure, as does types of cellular stress},
author = {Simon Couly and Yuko Yasui and Semnyonga Foncham and Ioannis Grammatikakis and Ashish Lal and Lei Shi and Tsung-Ping Su},
url = {https://pubmed.ncbi.nlm.nih.gov/38191696/},
doi = {10.1007/s00018-023-05023-z},
issn = {1420-9071},
year = {2024},
date = {2024-01-01},
urldate = {2024-01-01},
journal = {Cell Mol Life Sci},
volume = {81},
number = {1},
pages = {14},
abstract = {Sigma-1 receptor (S1R) is a calcium-sensitive, ligand-operated receptor chaperone present on the endoplasmic reticulum (ER) membrane. S1R plays an important role in ER-mitochondrial inter-organelle calcium signaling and cell survival. S1R and its agonists confer resilience against various neurodegenerative diseases; however, the molecular mechanism of S1R is not yet fully understood. At resting state, S1R is either in a monomeric or oligomeric state but the ratio of these concentrations seems to change upon activation of S1R. S1R is activated by either cellular stress, such as ER-calcium depletion, or ligands. While the effect of ligands on S1R quaternary structure remains unclear, the effect of cellular stress has not been studied. In this study we utilize cellular and an in-vivo model to study changes in quaternary structure of S1R upon activation. We incubated cells with cellular stressors (HO and thapsigargin) or exogenous ligands, then quantified monomeric and oligomeric forms. We observed that benzomorphan-based S1R agonists induce monomerization of S1R and decrease oligomerization, which was confirmed in the liver tissue of mice injected with (+)-Pentazocine. Antagonists block this effect but do not induce any changes when used alone. Oxidative stress (HO) increases the monomeric/oligomeric S1R ratio whereas ER calcium depletion (thapsigargin) has no effect. We also analyzed the oligomerization ability of various truncated S1R fragments and identified the fragments favorizing oligomerization. In this publication we demonstrate that quaternary structural changes differ according to the mechanism of S1R activation. Therefore, we offer a novel perspective on S1R activation as a nuanced phenomenon dependent on the type of stimulus.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2023
@article{pmid35507432,
title = {Nucleoporin POM121 signals TFEB-mediated autophagy via activation of SIGMAR1/sigma-1 receptor chaperone by pridopidine},
author = {Shao-Ming Wang and Hsiang-En Wu and Yuko Yasui and Michal Geva and Michael Hayden and Tangui Maurice and Mauro Cozzolino and Tsung-Ping Su},
url = {https://pubmed.ncbi.nlm.nih.gov/35507432/},
doi = {10.1080/15548627.2022.2063003},
issn = {1554-8635},
year = {2023},
date = {2023-01-01},
urldate = {2023-01-01},
journal = {Autophagy},
volume = {19},
number = {1},
pages = {126--151},
abstract = {Macroautophagy/autophagy is an essential process for cellular survival and is implicated in many diseases. A critical step in autophagy is the transport of the transcription factor TFEB from the cytosol into the nucleus, through the nuclear pore (NP) by KPNB1/importinβ1. In the C9orf72 subtype of amyotrophic lateral sclerosis-frontotemporal lobar degeneration (ALS-FTD), the hexanucleotide (G4C2)RNA expansion (HRE) disrupts the nucleocytoplasmic transport of TFEB, compromising autophagy. Here we show that a molecular chaperone, the SIGMAR1/Sigma-1 receptor (sigma non-opioid intracellular receptor 1), facilitates TFEB transport into the nucleus by chaperoning the NP protein (i.e., nucleoporin) POM121 which recruits KPNB1. In NSC34 cells, HRE reduces TFEB transport by interfering with the association between SIGMAR1 and POM121, resulting in reduced nuclear levels of TFEB, KPNB1, and the autophagy marker LC3-II. Overexpression of SIGMAR1 or POM121, or treatment with the highly selective and potent SIGMAR1 agonist pridopidine, currently in phase 2/3 clinical trials for ALS and Huntington disease, rescues all of these deficits. Our results implicate nucleoporin POM121 not merely as a structural nucleoporin, but also as a chaperone-operated signaling molecule enabling TFEB-mediated autophagy. Our data suggest the use of SIGMAR1 agonists, such as pridopidine, for therapeutic development of diseases in which autophagy is impaired.: ALS-FTD, amyotrophic lateral sclerosis-frontotemporal dementiaC9ALS-FTD, C9orf72 subtype of amyotrophic lateral sclerosis-frontotemporal dementiaCS, citrate synthaseER, endoplasmic reticulumGSS, glutathione synthetaseHRE, hexanucleotide repeat expansionHSPA5/BiP, heat shock protein 5LAMP1, lysosomal-associated membrane protein 1MAM, mitochondria-associated endoplasmic reticulum membraneMAP1LC3/LC3, microtubule-associated protein 1 light chain 3NP, nuclear poreNSC34, mouse motor neuron-like hybrid cell lineNUPs, nucleoporinsPOM121, nuclear pore membrane protein 121SIGMAR1/Sigma-1R, sigma non-opioid intracellular receptor 1TFEB, transcription factor EBTMEM97/Sigma-2R, transmembrane protein 97.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2022
@article{pmid35138910,
title = {Activation of the sigma-1 receptor chaperone alleviates symptoms of Wolfram syndrome in preclinical models},
author = {Lucie Crouzier and Alberto Danese and Yuko Yasui and Elodie M Richard and Jean-Charles Liévens and Simone Patergnani and Simon Couly and Camille Diez and Morgane Denus and Nicolas Cubedo and Mireille Rossel and Marc Thiry and Tsung-Ping Su and Paolo Pinton and Tangui Maurice and Benjamin Delprat},
url = {https://pubmed.ncbi.nlm.nih.gov/35138910/},
doi = {10.1126/scitranslmed.abh3763},
issn = {1946-6242},
year = {2022},
date = {2022-02-01},
urldate = {2022-02-01},
journal = {Sci Transl Med},
volume = {14},
number = {631},
pages = {eabh3763},
abstract = {The Wolfram syndrome is a rare autosomal recessive disease affecting many organs with life-threatening consequences; currently, no treatment is available. The disease is caused by mutations in the gene, coding for the protein wolframin, an endoplasmic reticulum (ER) transmembrane protein involved in contacts between ER and mitochondria termed as mitochondria-associated ER membranes (MAMs). Inherited mutations usually reduce the protein's stability, altering its homeostasis and ultimately reducing ER to mitochondria calcium ion transfer, leading to mitochondrial dysfunction and cell death. In this study, we found that activation of the sigma-1 receptor (S1R), an ER-resident protein involved in calcium ion transfer, could counteract the functional alterations of MAMs due to wolframin deficiency. The S1R agonist PRE-084 restored calcium ion transfer and mitochondrial respiration in vitro, corrected the associated increased autophagy and mitophagy, and was able to alleviate the behavioral symptoms observed in zebrafish and mouse models of the disease. Our findings provide a potential therapeutic strategy for treating Wolfram syndrome by efficiently boosting MAM function using the ligand-operated S1R chaperone. Moreover, such strategy might also be relevant for other degenerative and mitochondrial diseases involving MAM dysfunction.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2020
@article{Lee:2020aa,
title = {Sigma-1 receptor chaperones rescue nucleocytoplasmic transport deficit seen in cellular and Drosophila ALS/FTD models},
author = {Pin-Tse Lee and Jean-Charles Liévens and Shao-Ming Wang and Jian-Ying Chuang and Bilal Khalil and Hsiang-en Wu and Wen-Chang Chang and Tangui Maurice and Tsung-Ping Su},
url = {https://pubmed.ncbi.nlm.nih.gov/33149115/},
doi = {10.1038/s41467-020-19396-3},
isbn = {2041-1723},
year = {2020},
date = {2020-01-01},
journal = {Nature Communications},
volume = {11},
number = {1},
pages = {5580},
abstract = {In a subgroup of patients with amyotrophic lateral sclerosis (ALS)/Frontotemporal dementia (FTD), the (G4C2)-RNA repeat expansion from C9orf72 chromosome binds to the Ran-activating protein (RanGAP) at the nuclear pore, resulting in nucleocytoplasmic transport deficit and accumulation of Ran in the cytosol. Here, we found that the sigma-1 receptor (Sig-1R), a molecular chaperone, reverses the pathological effects of (G4C2)-RNA repeats in cell lines and in Drosophila. The Sig-1R colocalizes with RanGAP and nuclear pore proteins (Nups) and stabilizes the latter. Interestingly, Sig-1Rs directly bind (G4C2)-RNA repeats. Overexpression of Sig-1Rs rescues, whereas the Sig-1R knockout exacerbates, the (G4C2)-RNA repeats-induced aberrant cytoplasmic accumulation of Ran. In Drosophila, Sig-1R (but not the Sig-1R-E102Q mutant) overexpression reverses eye necrosis, climbing deficit, and firing discharge caused by (G4C2)-RNA repeats. These results on a molecular chaperone at the nuclear pore suggest that Sig-1Rs may benefit patients with C9orf72 ALS/FTD by chaperoning the nuclear pore assembly and sponging away deleterious (G4C2)-RNA repeats.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2016
@article{Su2016,
title = {The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems.},
author = {Tsung-Ping Su and Tzu-Chieh Su and Yoki Nakamura and Shang-Yi Tsai},
url = {https://www.ncbi.nlm.nih.gov/pubmed/26869505},
doi = {10.1016/j.tips.2016.01.003},
issn = {1873-3735 (Electronic); 0165-6147 (Linking)},
year = {2016},
date = {2016-04-01},
journal = {Trends Pharmacol Sci},
volume = {37},
number = {4},
pages = {262--278},
address = {Cellular Pathobiology Section, Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224, USA. Electronic address: TSU@intra.nida.nih.gov.},
abstract = {The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum (ER) protein that resides specifically in the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), an interface between ER and mitochondria. In addition to being able to translocate to the plasma membrane (PM) to interact with ion channels and other receptors, Sig-1R also occurs at the nuclear envelope, where it recruits chromatin-remodeling factors to affect the transcription of genes. Sig-1Rs have also been reported to interact with other membranous or soluble proteins at other loci, including the cytosol, and to be involved in several central nervous system (CNS) diseases. Here, we propose that Sig-1R is a pluripotent modulator with resultant multiple functional manifestations in living systems.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2015
@article{Tsai2015,
title = {Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope.},
author = {Shang-Yi A Tsai and Jian-Ying Chuang and Meng-Shan Tsai and Xiao-Fei Wang and Zheng-Xiong Xi and Jan-Jong Hung and Wen-Chang Chang and Antonello Bonci and Tsung-Ping Su},
url = {http://www.ncbi.nlm.nih.gov/pubmed/26554014},
doi = {10.1073/pnas.1518894112},
issn = {1091-6490 (Electronic); 0027-8424 (Linking)},
year = {2015},
date = {2015-11-24},
journal = {Proc Natl Acad Sci U S A},
volume = {112},
number = {47},
pages = {E6562-70},
address = {Cellular Pathobiology Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224;},
abstract = {The sigma-1 receptor (Sig-1R) chaperone at the endoplasmic reticulum (ER) plays important roles in cellular regulation. Here we found a new function of Sig-1R, in that it translocates from the ER to the nuclear envelope (NE) to recruit chromatin-remodeling molecules and regulate the gene transcription thereof. Sig-1Rs mainly reside at the ER-mitochondrion interface. However, on stimulation by agonists such as cocaine, Sig-1Rs translocate from ER to the NE, where Sig-1Rs bind NE protein emerin and recruit chromatin-remodeling molecules, including lamin A/C, barrier-to-autointegration factor (BAF), and histone deacetylase (HDAC), to form a complex with the gene repressor specific protein 3 (Sp3). Knockdown of Sig-1Rs attenuates the complex formation. Cocaine was found to suppress the gene expression of monoamine oxidase B (MAOB) in the brain of wild-type but not Sig-1R knockout mouse. A single dose of cocaine (20 mg/kg) in rats suppresses the level of MAOB at nuclear accumbens without affecting the level of dopamine transporter. Daily injections of cocaine in rats caused behavioral sensitization. Withdrawal from cocaine in cocaine-sensitized rats induced an apparent time-dependent rebound of the MAOB protein level to about 200% over control on day 14 after withdrawal. Treatment of cocaine-withdrawn rats with the MAOB inhibitor deprenyl completely alleviated the behavioral sensitization to cocaine. Our results demonstrate a role of Sig-1R in transcriptional regulation and suggest cocaine may work through this newly discovered genomic action to achieve its addictive action. Results also suggest the MAOB inhibitor deprenyl as a therapeutic agent to block certain actions of cocaine during withdrawal.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{Tsai2015,
title = {Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid.},
author = {Shang-Yi A Tsai and Michael J Pokrass and Neal R Klauer and Hiroshi Nohara and Tsung-Ping Su},
url = {https://www.ncbi.nlm.nih.gov/pubmed/25964330},
doi = {10.1073/pnas.1422001112},
issn = {1091-6490 (Electronic); 0027-8424 (Linking)},
year = {2015},
date = {2015-05-26},
journal = {Proc Natl Acad Sci U S A},
volume = {112},
number = {21},
pages = {6742--6747},
address = {Cellular Pathobiology Section, Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, MD 21224 stsai@intra.nida.nih.gov tsu@intra.nida.nih.gov.},
abstract = {Dysregulation of cyclin-dependent kinase 5 (cdk5) per relative concentrations of its activators p35 and p25 is implicated in neurodegenerative diseases. P35 has a short t(1/2) and undergoes rapid proteasomal degradation in its membrane-bound myristoylated form. P35 is converted by calpain to p25, which, along with an extended t(1/2), promotes aberrant activation of cdk5 and causes abnormal hyperphosphorylation of tau, thus leading to the formation of neurofibrillary tangles. The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum chaperone that is implicated in neuronal survival. However, the specific role of the Sig-1R in neurodegeneration is unclear. Here we found that Sig-1Rs regulate proper tau phosphorylation and axon extension by promoting p35 turnover through the receptor's interaction with myristic acid. In Sig-1R-KO neurons, a greater accumulation of p35 is seen, which results from neither elevated transcription of p35 nor disrupted calpain activity, but rather to the slower degradation of p35. In contrast, Sig-1R overexpression causes a decrease of p35. Sig-1R-KO neurons exhibit shorter axons with lower densities. Myristic acid is found here to bind Sig-1R as an agonist that causes the dissociation of Sig-1R from its cognate partner binding immunoglobulin protein. Remarkably, treatment of Sig-1R-KO neurons with exogenous myristic acid mitigates p35 accumulation, diminishes tau phosphorylation, and restores axon elongation. Our results define the involvement of Sig-1Rs in neurodegeneration and provide a mechanistic explanation that Sig-1Rs help maintain proper tau phosphorylation by potentially carrying and providing myristic acid to p35 for enhanced p35 degradation to circumvent the formation of overreactive cdk5/p25.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2013
@article{Kourrich2013,
title = {Dynamic interaction between sigma-1 receptor and Kv1.2 shapes neuronal and behavioral responses to cocaine.},
author = {Said Kourrich and Teruo Hayashi and Jian-Ying Chuang and Shang-Yi Tsai and Tsung-Ping Su and Antonello Bonci},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23332758},
doi = {10.1016/j.cell.2012.12.004},
issn = {1097-4172 (Electronic); 0092-8674 (Linking)},
year = {2013},
date = {2013-01-17},
journal = {Cell},
volume = {152},
number = {1-2},
pages = {236--247},
address = {Cellular Neurobiology Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA.},
abstract = {The sigma-1 receptor (Sig-1R), an endoplasmic reticulum (ER) chaperone protein, is an interorganelle signaling modulator that potentially plays a role in drug-seeking behaviors. However, the brain site of action and underlying cellular mechanisms remain unidentified. We found that cocaine exposure triggers a Sig-1R-dependent upregulation of D-type K(+) current in the nucleus accumbens (NAc) that results in neuronal hypoactivity and thereby enhances behavioral cocaine response. Combining ex vivo and in vitro studies, we demonstrated that this neuroadaptation is caused by a persistent protein-protein association between Sig-1Rs and Kv1.2 channels, a phenomenon that is associated to a redistribution of both proteins from intracellular compartments to the plasma membrane. In conclusion, the dynamic Sig-1R-Kv1.2 complex represents a mechanism that shapes neuronal and behavioral response to cocaine. Functional consequences of Sig-1R binding to K(+) channels may have implications for other chronic diseases where maladaptive intrinsic plasticity and Sig-1Rs are engaged.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2009
@article{Tsai2009,
title = {Sigma-1 receptors regulate hippocampal dendritic spine formation via a free radical-sensitive mechanism involving Rac1xGTP pathway.},
author = {Shang-Yi Tsai and Teruo Hayashi and Brandon K Harvey and Yun Wang and Wells W Wu and Rong-Fong Shen and Yongqing Zhang and Kevin G Becker and Barry J Hoffer and Tsung-Ping Su},
url = {https://www.ncbi.nlm.nih.gov/pubmed/20018732},
doi = {10.1073/pnas.0909089106},
issn = {1091-6490 (Electronic); 0027-8424 (Linking)},
year = {2009},
date = {2009-12-29},
journal = {Proc Natl Acad Sci U S A},
volume = {106},
number = {52},
pages = {22468--22473},
address = {Cellular Pathobiology Section, Cellular Neurobiology Research Branch, National Institute on Drug Abuse, 333 Cassell Drive, Baltimore, MD 21224, USA.},
abstract = {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 Rac1.GTP. 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 Rac1.GTP, also reverses the siRNA-induced dendritic spine deficits. In addition, constitutively active Rac1.GTP reverses this deficit. These results implicate Sig-1Rs as endogenous regulators of hippopcampal dendritic spine formation and suggest a free radical-sensitive ER-mitochondrion-Rac1.GTP pathway in the regulation of dendritic spine formation in the hippocampus.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2007
@article{Hayashi2007,
title = {Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival.},
author = {Teruo Hayashi and Tsung-Ping Su},
url = {https://www.ncbi.nlm.nih.gov/pubmed/17981125},
doi = {10.1016/j.cell.2007.08.036},
issn = {0092-8674 (Print); 0092-8674 (Linking)},
year = {2007},
date = {2007-11-02},
journal = {Cell},
volume = {131},
number = {3},
pages = {596--610},
address = {Cellular Pathobiology Unit, Plasticity and Development Section, Cellular Neurobiology Research Branch, Intramural Research Program, NIDA, NIH, DHHS, Baltimore, MD 21224, USA. thayashi@intra.nida.nih.gov},
abstract = {Communication between the endoplasmic reticulum (ER) and mitochondrion is important for bioenergetics and cellular survival. The ER supplies Ca(2+) directly to mitochondria via inositol 1,4,5-trisphosphate receptors (IP3Rs) at close contacts between the two organelles referred to as mitochondrion-associated ER membrane (MAM). We found here that the ER protein sigma-1 receptor (Sig-1R), which is implicated in neuroprotection, carcinogenesis, and neuroplasticity, is a Ca(2+)-sensitive and ligand-operated receptor chaperone at MAM. Normally, Sig-1Rs form a complex at MAM with another chaperone, BiP. Upon ER Ca(2+) depletion or via ligand stimulation, Sig-1Rs dissociate from BiP, leading to a prolonged Ca(2+) signaling into mitochondria via IP3Rs. Sig-1Rs can translocate under chronic ER stress. Increasing Sig-1Rs in cells counteracts ER stress response, whereas decreasing them enhances apoptosis. These results reveal that the orchestrated ER chaperone machinery at MAM, by sensing ER Ca(2+) concentrations, regulates ER-mitochondrial interorganellar Ca(2+) signaling and cell survival.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2004
@article{Hayashi2004,
title = {Sigma-1 receptors at galactosylceramide-enriched lipid microdomains regulate oligodendrocyte differentiation.},
author = {Teruo Hayashi and Tsung-Ping Su},
url = {https://www.ncbi.nlm.nih.gov/pubmed/15466698},
doi = {10.1073/pnas.0402890101},
issn = {0027-8424 (Print); 0027-8424 (Linking)},
year = {2004},
date = {2004-10-12},
journal = {Proc Natl Acad Sci U S A},
volume = {101},
number = {41},
pages = {14949--14954},
address = {Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, U.S. Department of Health and Human Services, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.},
abstract = {In the brain, myelin is important in regulating nerve conduction and neurotransmitter release by providing insulation at axons. Myelin is a specialized yet continuous sheet structure of differentiated oligodendrocytes (OLs) that is enriched in lipids, specifically galactosylceramides (GalCer) originated at the endoplasmic reticulum (ER). GalCer are known to affect OL differentiation. However, the mechanism whereby GalCer affect OL differentiation is not well understood. Sigma-1 receptors (Sig-1Rs), shown by us to exist in detergent-insoluble lipid microdomains at lipid-enriched loci of ER in NG108 cells, are important in the compartmentalization/transport of ER-synthesized lipids and in cellular differentiation. In this study, we used rat primary hippocampal cultures and found that Sig-1Rs form GalCer-enriched lipid rafts at ER lipid droplet-like structures in the entire myelin sheet of mature OLs. In rat OL progenitors (CG-4 cells), levels of lipid raft-residing Sig-1Rs and GalCer increase as cells differentiate. Sig-1Rs also increase in OLs and myelin of developing rat brains. Sig-1R, GalCer, and cholesterol are colocalized and are resistant to the Triton X-100 solubilization. Treating cells with a Sig-1R agonist or targeting Sig-1Rs at lipid rafts by overexpression of Sig-1Rs in CG-4 cells enhances differentiation, whereas reducing Sig-1Rs at lipid rafts by transfection of functionally dominant-negative Sig-1Rs attenuates differentiation. Furthermore, Sig-1R siRNA inhibits differentiation. Our findings indicate that, in the brain, Sig-1Rs targeting GalCer-containing lipid microdomains are important for OL differentiation and that Sig-1Rs may play an important role in the pathogenesis of certain demyelinating diseases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2001
@article{Hayashi2001,
title = {Regulating ankyrin dynamics: Roles of sigma-1 receptors.},
author = {T Hayashi and T P Su},
url = {https://www.ncbi.nlm.nih.gov/pubmed/11149946},
doi = {10.1073/pnas.021413698},
issn = {0027-8424 (Print); 0027-8424 (Linking)},
year = {2001},
date = {2001-01-16},
journal = {Proc Natl Acad Sci U S A},
volume = {98},
number = {2},
pages = {491--496},
address = {Cellular Pathobiology Unit, Cellular Neurobiology Research Branch, Intramural Research Program, National Institute on Drug Abuse/National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.},
abstract = {Ankyrin is a cytoskeletal adaptor protein that controls important cellular functions, including Ca(2+) efflux at inositol 1,4,5-trisphosphate receptors (IP(3)R) on the endoplasmic reticulum. The present study found that sigma-1 receptors (Sig-1R), unique endoplasmic reticulum proteins that bind certain steroids, neuroleptics, and psychotropic drugs, form a trimeric complex with ankyrin B and IP(3)R type 3 (IP(3)R-3) in NG-108 cells. The trimeric complex could be coimmunoprecipitated by antibodies against any of the three proteins. Sig-1R agonists such as pregnenolone sulfate and cocaine caused the dissociation of an ankyrin B isoform (ANK 220) from IP(3)R-3. This effect caused by Sig-1R agonists was blocked by a Sig-1R antagonist. The degree of dissociation of ANK 220 from IP(3)R-3 caused by Sig-1R ligands correlates excellently with the ligands' efficacies in potentiating the bradykinin-induced increase in cytosolic free Ca(2+) concentration. Immunocytohistochemistry showed that Sig-1R, ankyrin B, and IP(3)R-3 are colocalized in NG-108 cells in perinuclear areas and in regions of cell-to-cell communication. These results suggest that Sig-1R and associated ligands may play important roles in cells by controlling the function of cytoskeletal proteins and that the Sig-1R/ANK220/IP(3)R-3 complex regulating Ca(2+) signaling may represent a site of action for neurosteroids and cocaine.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
1988
@article{Su1988,
title = {Steroid binding at sigma receptors suggests a link between endocrine, nervous, and immune systems.},
author = {T P Su and E D London and J H Jaffe},
url = {https://www.ncbi.nlm.nih.gov/pubmed/2832949},
issn = {0036-8075 (Print); 0036-8075 (Linking)},
year = {1988},
date = {1988-04-08},
journal = {Science},
volume = {240},
number = {4849},
pages = {219--221},
address = {Addiction Research Center, National Institute on Drug Abuse, Baltimore, MD 21224.},
abstract = {Specific sigma binding sites have been identified in the mammalian brain and lymphoid tissue. In this study, certain gonadal and adrenal steroids, particularly progesterone, were found to inhibit sigma receptor binding in homogenates of brain and spleen. The findings suggest that steroids are naturally occurring ligands for sigma receptors and raise the possibility that these sites mediate some aspects of steroid-induced mental disturbances and alterations in immune functions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
