DOCSLIB.ORG

Sigma-1 Receptors Regulate Hippocampal Dendritic Spine Formation Via a Free Radical-Sensitive Mechanism Involving Rac1GTP Pathway

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Sigma-1 Receptors Regulate Hippocampal Dendritic Spine Formation Via a Free Radical-Sensitive Mechanism Involving Rac1�GTP Pathway Sigma-1 receptors regulate hippocampal dendritic spine formation via a free radical-sensitive mechanism involving Rac1⅐GTP pathway Shang-Yi Tsaia, Teruo Hayashia, Brandon K. Harveyb, Yun Wangb, Wells W. Wuc, Rong-Fong Shenc, Yongqing Zhangd, Kevin G. Beckerd, Barry J. Hoffere, and Tsung-Ping Sua,1 aCellular Pathobiology Section, Cellular Neurobiology Research Branch, and bNeural Protection and Regeneration Section, Molecular Neuropsychiatry Branch, Intramural Research Program, National Institute on Drug Abuse, 333 Cassell Drive, Baltimore, MD 21224; cProteomics and Analytical Biochemistry Unit and dGene Expression and Genomics Unit, Research Resources Branch, Intramural Research Program, National Institute on Aging, Biomedical Research Center, 251 Bayview Boulevard, National Institutes of Health, United States Department of Health and Human Services, Baltimore, MD 21224; and eCellular Neurophysiology Section, Cellular Neurobiology Research Branch, Intramural Research Program, National Institute on Drug Abuse, 333 Cassell Drive, Baltimore, MD 21224 Edited by Solomon Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved October 16, 2009 (received for review August 12, 2009) Sigma-1 receptors (Sig-1Rs) are endoplasmic reticulum (ER)-resident specific GEF TIAM1 regulate the late stage of neural morphogenesis proteins known to be involved in learning and memory. Dendritic by targeting themselves to dendritic spines and controlling the forma- spines in hippocampal neurons play important roles in neuroplasticity tion of mature forms of spines (8–10). TIAM1-Rac1⅐GTP signaling is and learning and memory. This study tested the hypothesis that also important for dendrite branching. Thus, Tiam1-Rac1⅐GTP signal- Sig-1Rs might regulate denritic spine formation in hippocampal neu- ing is critical for the morphogenesis of dendritic spines especially in the rons and examined potential mechanisms therein. In rat hippocampal later stages of neuronal maturation. primary neurons, the knockdown of Sig-1Rs by siRNAs causes a deficit Originally mistaken as a subtype of opioid receptors (11), the in the formation of dendritic spines that is unrelated to ER Ca2؉ Sigma-1 receptor (Sig-1R) (12–15) is now known to be a nonopioid signaling or apoptosis, but correlates with the mitochondrial perme- endoplasmic reticulum (ER)-resident protein (16–19). Sig-1Rs are ability transition and cytochrome c release, followed by caspase-3 postulated to be involved in neuropsychiatric diseases including activation, Tiam1 cleavage, and a reduction in Rac1⅐GTP. Sig-1R- amnesia and addiction (13, 20, 21). By using CHO cells, we recently knockdown neurons contain higher levels of free radicals when (17) identified the Sig-1R as a ligand-operated ER receptor chap- compared to control neurons. The activation of superoxide dismutase erone that regulates Ca2ϩ signaling specifically by chaperoning type or the application of the hydroxyl-free radical scavenger N-acetyl 3IP3 receptors. Importantly, Sig-1Rs regulate neuritogenesis in cysteine (NAC) to the Sig-1R-knockdown neurons rescues dendritic PC12 cells (22) and enhance cell differentiation in rat oligoden- spines and mitochondria from the deficits caused by Sig-1R siRNA. drocytes (23). Sig-1Rs also promote reconstitution of lipid rafts in Further, the caspase-3-resistant TIAM1 construct C1199DN, a stable plasma membranes (22). Taken together, these results suggest the guanine exchange factor able to constitutively activate Rac1 in the possibility that Sig-1Rs might affect the morphogenesis of neurons form of Rac1⅐GTP, also reverses the siRNA-induced dendritic spine in the CNS. However, this possibility has never been examined. deficits. In addition, constitutively active Rac1⅐GTP reverses this def- We tested if the ER Sig-1R might regulate neuronal morphology icit. These results implicate Sig-1Rs as endogenous regulators of in this study, specifically dendritic spine formation in rat primary hippopcampal dendritic spine formation and suggest a free radical- hippocampal neurons. We also examined potential underlying sensitive ER-mitochondrion-Rac1⅐GTP pathway in the regulation of mechanisms of such effect, if present. We report here that Sig-1Rs dendritic spine formation in the hippocampus. regulate dendritic spine formation via a potential ER-mitochon- drion-Rac⅐GTP pathway, apparently due to this receptor’s ability to mitochondria ͉ ROS ͉ N-acetyl cyteine ͉ learning and memory ͉ caspase-3 regulate the redox state of neurons. Results endritic spines in the CNS are important for many functions. DDendritic atrophy in the neocortical region is related to Sig-1Rs Regulate the Morphogenesis of Hippocampal Primary Neu- aging-induced amnesia, and its reversal improves memory retention rons. We examined the roles of Sig-1Rs in the morphogenesis of (1). Similarly, the loss of dendritic spine-related synapses is cur- hippocampal primary neurons in vitro by silencing Sig-1R expres- rently a strong pathologic correlate of cognitive decline, and sion using siRNAs. Small hairpin RNAs, constructed in the pSI- synaptic dysfunction is evident long before synapses and neurons REN vector, were transfected into primary neurons by using the are lost (2). On the other hand, exposure to drugs of abuse including liposome-delivering system in this initial portion of the study. Rat cocaine, nicotine, or morphine produces persistent changes, usually hippocampal primary neurons were thus transfected with siRNAs in the form of increased dendritic spines and arborizations, in cells (17, 23) together with pEGFP-N1 vectors on DIV 7. Morphologies in brain regions involved in incentive motivation and reward (3). were observed on DIV 14 or 21. Control neurons receiving These persistent changes are thought to represent the neuronal transfection of control siRNAs (siCon-tf) on DIV 14 showed a reorganization that contributes to some of the persistent sequelae associated with drug use, including the establishment of motiva- Author contributions: S.-Y.T., T.H., B.K.H., and T.-P.S. designed research; S.-Y.T., and T.H. tional conditioning and learning (3). performed research; B.K.H. and Y.W. contributed new reagents/analytic tools; S.-Y.T., T.H., The morphology of dendritic spines and axons is determined by the B.K.H., Y.W., W.W.W., R.-F.S., Y.Z., K.G.B., B.J.H., and T.-P.S. analyzed data; and S.-Y.T., T.H., dynamic cytoskeleton protein actin. Rho family small GTPases includ- B.J.H., and T.-P.S. wrote the paper. ing Rho, Cdc42, and Rac1 regulate the dynamics of actin and are critical The authors declare no conflict of interest. for neuronal polarization and morphogenesis (4–6). Rho proteins are This article is a PNAS Direct Submission. regulated by guanine nucleotide exchange factors (GEFs). In early Freely available online through the PNAS open access option. stages of neural morphogenesis, the activation of Cdc42 promotes the 1To whom correspondence should be addressed. E-mail: [email protected]. formation of filopodia, the long thin protrusions serving as primary This article contains supporting information online at www.pnas.org/cgi/content/full/ precursors of axons and dendritic spines (7). However, Rac1 and its 0909089106/DCSupplemental. 22468–22473 ͉ PNAS ͉ December 29, 2009 ͉ vol. 106 ͉ no. 52 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0909089106 Downloaded by guest on September 27, 2021 Fig. 1. Inhibition of dendritic morphogenesis in Sig-1R-knockdown hippocampal neurons. (A–F) Effects of siSig-1R-tf on dendrite formation. Neurons were transfected with siRNAs on DIV 7 and were stained on 14 or 22 DIV with anti-MAP-2B antibodies. The number of established primary dendrites and branches were counted. Primary dendrites are defined as neurites originating from the neuronal soma and are at least longer than two times the diameter of the cell body. (Scale bar, 100 ␮m.) ***P Ͻ 0.001; n ϭ 3, five to 10 neurons were quantified in each individual experiment. (G–J) Effect of siSig-1R-tf on spine formation. Neurons were transfected on DIV 7 with siCon (G and I) or siSig-1R (Hand J) vectors in combination with EGFP. Neurons were stained with rhodamin phalloidin for F-actin. Note elongated filopodia in si-Sig-1R-tf neurons. (Kand L) Quantitative assessments were made of the effects of siSig-1Rs on protrusion length, dendrite branching, and filopodium formation. The control neurons at DIV 22 had protrusions mostly Ͻ2␮m in length and mushroom shaped, which is characteristic of dendritic spines, whereas the siRNA neurons failed to retract protrusions (i.e., exhibited elongated filopodia). Protrusions equals dendritic spines plus filopodia. (Scale bar, 50 ␮m.) ***P ϭ 0.0002; n ϭ 2, at least 20 neurons were captured in each experiment, and two to three dendrites were randomly selected from each neuron for counting of protrusions. (M) Synaptophysin immunostaining. (N) Effects of siSig-1Rs on synaptic activity. FM4–64 (red)-labeled neurons were depolarized with KCl for measurement of synaptic activity. (Scale bars, M 20 ␮m and N 5 ␮m.) typical morphology of a stage V neuron, having several long the longer the culture time, the more pronounced the abnormal dendrites with tapering and branching characteristics (Fig. 1 A–F). phenotype was seen, such as increased numbers of elongated The Sig-1R-siRNA-transfected (siSig-1R-tf) neurons, however, filopodia-like protrusions lacking head structures. In general, si- showed a reduction of extension and branching of dendrites. Long lencing of Sig-1R expression increased the length of protrusions by filopodia-like structures protruding from soma were often observed 59% on DIV 16 and 159% on DIV 22, respectively. These results in siSig-1R-tf neurons. Similar effects were seen on DIV 21 in suggest a dysregulation of stage-dependent signalings for actin siSig-1R-tf neurons. Sig-1Rs also affected the formation and mat- compartmentalization/polymerization in Sig-1R-deficient neurons. uration of dendritic spines. Results are shown in Fig. 1 G–L.On DIV 16, control neurons formed filopodia-like long protrusions on Sig-1R-Knockdown Inhibits Synapse Formation. Active synapses ex- NEUROSCIENCE dendrites, with majority of them (Ͼ60%) showing F-actin-enriched press specific proteins and receptors for proper function.
Load more

Recommended publications
  • A Role for Sigma Receptors in Stimulant Self Administration and Addiction
    Pharmaceuticals 2011, 4, 880-914; doi:10.3390/ph4060880 OPEN ACCESS pharmaceuticals ISSN 1424-8247 www.mdpi.com/journal/pharmaceuticals Review A Role for Sigma Receptors in Stimulant Self Administration and Addiction Jonathan L. Katz *, Tsung-Ping Su, Takato Hiranita, Teruo Hayashi, Gianluigi Tanda, Theresa Kopajtic and Shang-Yi Tsai Psychobiology and Cellular Pathobiology Sections, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, 21224, USA * Author to whom correspondence should be addressed; E-Mail: [email protected]. Received: 16 May 2011; in revised form: 11 June 2011 / Accepted: 13 June 2011 / Published: 17 June 2011 Abstract: Sigma1 receptors (σ1Rs) represent a structurally unique class of intracellular proteins that function as chaperones. σ1Rs translocate from the mitochondria-associated membrane to the cell nucleus or cell membrane, and through protein-protein interactions influence several targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Several studies have demonstrated that σR antagonists block stimulant-induced behavioral effects, including ambulatory activity, sensitization, and acute toxicities. Curiously, the effects of stimulants have been blocked by σR antagonists tested under place-conditioning but not self-administration procedures, indicating fundamental differences in the mechanisms underlying these two effects. The self administration of σR agonists has been found in subjects previously trained to self administer cocaine. The reinforcing effects of the σR agonists were blocked by σR antagonists. Additionally, σR agonists were found to increase dopamine concentrations in the nucleus accumbens shell, a brain region considered important for the reinforcing effects of abused drugs.
    [Show full text]
  • Les Récepteurs Sigma : De Leur Découverte À La Mise En Évidence De Leur Implication Dans L’Appareil Cardiovasculaire
    P HARMACOLOGIE Les récepteurs sigma : de leur découverte à la mise en évidence de leur implication dans l’appareil cardiovasculaire ! L. Monassier*, P. Bousquet* RÉSUMÉ. Les récepteurs sigma constituent des entités protéiques dont les modalités de fonctionnement commencent à être comprises. Ils sont ciblés par de nombreux ligands dont certains, comme l’halopéridol, sont des psychotropes, mais aussi par des substances connues comme anti- arythmiques cardiaques : l’amiodarone ou le clofilium. Ils sont impliqués dans diverses fonctions cardiovasculaires telles que la contractilité et le rythme cardiaque, ainsi que dans la régulation de la vasomotricité artérielle (coronaire et systémique). Nous tentons dans cette brève revue de faire le point sur quelques-uns des aspects concernant les ligands, les sites de liaison, les voies de couplage et les fonctions cardio- vasculaires de ces récepteurs énigmatiques. Mots-clés : Récepteurs sigma - Contractilité cardiaque - Troubles du rythme - Vasomotricité - Protéines G - Canaux potassiques. a possibilité de l’existence d’un nouveau récepteur RÉCEPTEURS SIGMA (σ) constitue toujours un moment d’exaltation pour le Historique L pharmacologue. La perspective de la conception d’un nouveau pharmacophore, d’identifier des voies de couplage et, La description initiale des récepteurs σ en faisait un sous-type par là, d’aborder la physiologie puis rapidement la physio- de récepteurs des opiacés. Cette classification provenait des pathologie, émerge dès que de nouveaux sites de liaison sont effets d’un opiacé synthétique, la (±)-N-allylnormétazocine décrits pour la première fois. L’aventure des “récepteurs sigma” (SKF-10,047), qui ne pouvaient pas être tous attribués à ses (σ) ne déroge pas à cette règle puisque, initialement décrits par actions sur les récepteurs µ et κ.
    [Show full text]
  • Structural Insights Into Σ1 Receptor Interactions with Opioid Ligands by Molecular Dynamics Simulations
    Article Structural Insights into σ1 Receptor Interactions with Opioid Ligands by Molecular Dynamics Simulations Mateusz Kurciński 1,*, Małgorzata Jarończyk 2, Piotr F. J. Lipiński 3, Jan Cz. Dobrowolski 2 and Joanna Sadlej 2,4,* 1 Faculty of Chemistry, University of Warsaw, Pasteur Str.1, 02-093 Warsaw, Poland 2 National Medicines Institute, 30/34 Chełmska Str., 00-725 Warsaw, Poland; [email protected] (M.J.); [email protected] (J.C.D.) 3 Department of Neuropeptides, Mossakowski Medical Research Center, Polish Academy of Sciences, 02-106 Warsaw, Poland; [email protected] 4 Faculty of Mathematics and Natural Sciences. Cardinal Stefan Wyszyński University,1/3 Wóycickiego Str., 01-938 Warsaw, Poland * Correspondence: [email protected] (M.K.); [email protected] (J.S.); Tel.: +48-225-526-364 (M.K.); +48-225-526-396 (J.S.) Received: 17 January 2018; Accepted: 16 February 2018; Published: 18 February 2018 Abstract: Despite considerable advances over the past years in understanding the mechanisms of action and the role of the σ1 receptor, several questions regarding this receptor remain unanswered. This receptor has been identified as a useful target for the treatment of a diverse range of diseases, from various central nervous system disorders to cancer. The recently solved issue of the crystal structure of the σ1 receptor has made elucidating the structure–activity relationship feasible. The interaction of seven representative opioid ligands with the crystal structure of the σ1 receptor (PDB ID: 5HK1) was simulated for the first time using molecular dynamics (MD). Analysis of the MD trajectories has provided the receptor–ligand interaction fingerprints, combining information on the crucial receptor residues and frequency of the residue–ligand contacts.
    [Show full text]
  • Involvement of the Sigma-1 Receptor in Methamphetamine-Mediated Changes to Astrocyte Structure and Function" (2020)
    University of Kentucky UKnowledge Theses and Dissertations--Medical Sciences Medical Sciences 2020 Involvement of the Sigma-1 Receptor in Methamphetamine- Mediated Changes to Astrocyte Structure and Function Richik Neogi University of Kentucky, [email protected] Author ORCID Identifier: https://orcid.org/0000-0002-8716-8812 Digital Object Identifier: https://doi.org/10.13023/etd.2020.363 Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Neogi, Richik, "Involvement of the Sigma-1 Receptor in Methamphetamine-Mediated Changes to Astrocyte Structure and Function" (2020). Theses and Dissertations--Medical Sciences. 12. https://uknowledge.uky.edu/medsci_etds/12 This Master's Thesis is brought to you for free and open access by the Medical Sciences at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Medical Sciences by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known.
    [Show full text]
  • The Use of Stems in the Selection of International Nonproprietary Names (INN) for Pharmaceutical Substances
    WHO/PSM/QSM/2006.3 The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances 2006 Programme on International Nonproprietary Names (INN) Quality Assurance and Safety: Medicines Medicines Policy and Standards The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 © World Health Organization 2006 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: [email protected]). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
    [Show full text]
  • Sigma-I and Sigma-2 Receptors Are Expressed in a Wide Variety of Human and Rodent Tumor Cell Lines
    [CANCERRESEARCH55, 408-413, January 15, 19951 Sigma-i and Sigma-2 Receptors Are Expressed in a Wide Variety of Human and Rodent Tumor Cell Lines Bertold J. Vilner, Christy S. John, and Wayne D. Bowen' Unit on Receptor Biochemistry and Pharmacology, Laboratory of Medicinal Chemistry, National Institute of Diabetes Digestive and Kidney Diseases, National institutes of Health, Bethesda, Maryland 20892 [B. J. V.. W. D. B.], and Radiopharmaceutical Chemistry Section, Department of Radiology, The George Washington University Medical Center, Washington, DC 20037 (C. S .1.1 ABSTRACT Sigma receptors occur in at least two classes which are distinguish able both pharmacologically and by molecular properties (1, 8—10). Thirteen tumor-derived cell lines of human and nonhuman origin and The prototypic sigma ligands, haloperidol, DTG,2 and (+)-3-PPP do from various tissues were examined for the presence and density of not strongly differentiate the sites. However, sigma-i sites are readily sigma-i and sigma-2 receptors. Sigma-i receptors of a crude membrane fraction were labeled using [3H](+)-pentazocine, and sigma-2 receptors distinguished from sigma-2 sites on the basis of their affinity for were labeled with [3H11,3-di-o-tolylguanidine ([3HJDTG); in the presence benzomorphan-type opiates such as pentazocine and SKF 10,047. or absence ofdextrallorphan. [3H](+)-Pentazocine-bindingsites were het Sigma-i receptors exhibit high affinity for (+)-benzomorphans and erogeneous. In rodent cell lines (e.g., C6 glioma, N1E-115 neuroblastoma, lower affinity for the corresponding (—)-enantiomer.Sigma-2 recep and NG1OS—15neuroblastoma x glioma hybrid), human T47D breast tors show the opposite enantioselectivity, having very low affinity for ductal careinoma, human NCI-H727 lung carcinold, and hwnan A375 (+)-benzomorphans.
    [Show full text]
  • Dopamine Release from Rat Striatum Via Σ Receptors
    0022-3565/03/3063-934–940$7.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 306, No. 3 Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics 52324/1083036 JPET 306:934–940, 2003 Printed in U.S.A. Steroids Modulate N-Methyl-D-aspartate-Stimulated [3H]Dopamine Release from Rat Striatum via ␴ Receptors SAMER J. NUWAYHID and LINDA L. WERLING Department of Pharmacology, George Washington University Medical Center, Washington, DC Received March 31, 2003; accepted May 13, 2003 ABSTRACT Steroids have been proposed as endogenous ligands at ␴ indol-3-yl]-1-butyl]spiro[iso-benzofuran-1(3H), 4Јpiperidine] Downloaded from receptors. In the current study, we examined the ability of (Lu28-179). Lastly, to determine whether a protein kinase C (PKC) steroids to regulate N-methyl-D-aspartate (NMDA)-stimulated signaling system might be involved in the inhibition of NMDA- [3H]dopamine release from slices of rat striatal tissue. We found stimulated [3H]dopamine release, we tested the PKC␤-selective that both progesterone and pregnenolone inhibit [3H]dopamine inhibitor 5,21:12,17-dimetheno-18H-dibenzo[i,o]pyrrolo[3,4– release in a concentration-dependent manner similarly to pro- 1][1,8]diacyclohexadecine-18,20(19H)-dione,8-[(dimethylamin- totypical agonists, such as (ϩ)-pentazocine. The inhibition seen o)methyl]-6,7,8,9,10,11-hexahydro-monomethanesulfonate (9Cl) jpet.aspetjournals.org by both progesterone and pregnenolone exhibits IC50 values (LY379196) against both progesterone and pregnenolone. We consistent with reported Ki values for these steroids obtained in found that LY379196 at 30 nM reversed the inhibition of release by ␴ binding studies, and was fully reversed by both the 1 antagonist both progesterone and pregnenolone.
    [Show full text]
  • Cardiac Sigma Receptors – an Update
    Physiol. Res. 67 (Suppl. 4): S561-S576, 2018 https://doi.org/10.33549/physiolres.934052 REVIEW Cardiac Sigma Receptors – An Update T. STRACINA1, M. NOVAKOVA1 1Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic Received March 25, 2018 Accepted September 12, 2018 Summary (Martin et al. 1976). The authors believed that sigma More than four decades passed since sigma receptors were first receptor represents an opioid receptor subtype, which mentioned. Since then, existence of at least two receptor mediates psychomimetic and stimulatory behavioral subtypes and their tissue distributions have been proposed. effects of N-allylnormetazocine (SKF-10047) in chronic Nowadays, it is clear, that sigma receptors are unique ubiquitous spinal dog. Subsequent binding studies in guinea pig and proteins with pluripotent function, which can interact with so rat showed that binding profile of sigma receptor differs many different classes of proteins. As the endoplasmic resident from any other known subtype of opioid receptor as well proteins, they work as molecular chaperones – accompany as other receptor classes (Su 1982, Tam 1983). Therefore, various proteins during their folding, ensure trafficking of the the sigma receptor was defined as novel receptor type maturated proteins between cellular organelles and regulate their (Su 1982). functions. In the heart, sigma receptor type 1 is more dominant. Cardiac sigma 1 receptors regulate response to endoplasmic Two subtypes of sigma receptor reticulum stress, modulates calcium signaling in cardiomyocyte Further research led to differentiation among at and can affect function of voltage-gated ion channels. They least two subtypes of sigma receptors. Based on their contributed in pathophysiology of cardiac hypertrophy, heart diverse ligand selectivity and stereospecificity, association failure and many other cardiovascular disorders.
    [Show full text]
  • Pharmacology and Therapeutic Potential of Sigma1 Receptor Ligands E.J
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central 344 Current Neuropharmacology, 2008, 6, 344-366 Pharmacology and Therapeutic Potential of Sigma1 Receptor Ligands E.J. Cobos1,2, J.M. Entrena1, F.R. Nieto1, C.M. Cendán1 and E. Del Pozo1,* 1Department of Pharmacology and Institute of Neuroscience, Faculty of Medicine, and 2Biomedical Research Center, University of Granada, Granada, Spain Abstract: Sigma () receptors, initially described as a subtype of opioid receptors, are now considered unique receptors. Pharmacological studies have distinguished two types of receptors, termed 1 and 2. Of these two subtypes, the 1 re- ceptor has been cloned in humans and rodents, and its amino acid sequence shows no homology with other mammalian proteins. Several psychoactive drugs show high to moderate affinity for 1 receptors, including the antipsychotic haloperi- dol, the antidepressant drugs fluvoxamine and sertraline, and the psychostimulants cocaine and methamphetamine; in ad- dition, the anticonvulsant drug phenytoin allosterically modulates 1 receptors. Certain neurosteroids are known to interact with 1 receptors, and have been proposed to be their endogenous ligands. These receptors are located in the plasma membrane and in subcellular membranes, particularly in the endoplasmic reticulum, where they play a modulatory role in 2+ intracellular Ca signaling. Sigma1 receptors also play a modulatory role in the activity of some ion channels and in sev- eral neurotransmitter systems, mainly in glutamatergic neurotransmission. In accordance with their widespread modula- tory role, 1 receptor ligands have been proposed to be useful in several therapeutic fields such as amnesic and cognitive deficits, depression and anxiety, schizophrenia, analgesia, and against some effects of drugs of abuse (such as cocaine and methamphetamine).
    [Show full text]
  • The Impact of the Neuropeptide Substance P (SP) Fragment SP1-7 on Chronic Neuropathic Pain
    Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 198 The Impact of the Neuropeptide Substance P (SP) Fragment SP1-7 on Chronic Neuropathic Pain ANNA JONSSON ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6192 ISBN 978-91-554-9206-9 UPPSALA urn:nbn:se:uu:diva-241637 2015 Dissertation presented at Uppsala University to be publicly examined in B21, BMC, Husargatan 3, Uppsala, Friday, 8 May 2015 at 09:15 for the degree of Doctor of Philosophy (Faculty of Pharmacy). The examination will be conducted in English. Faculty examiner: Professor of Medicine James Zadina (Tulane University School of Medicine, New Orleans, USA). Abstract Jonsson, A. 2015. The Impact of the Neuropeptide Substance P (SP) Fragment SP1-7 on Chronic Neuropathic Pain. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 198. 64 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9206-9. There is an unmet medical need for the efficient treatment of neuropathic pain, a condition that affects approximately 10% of the population worldwide. Current therapies need to be improved due to the associated side effects and lack of response in many patients. Moreover, neuropathic pain causes great suffering to patients and puts an economical burden on society. The work presented in this thesis addresses SP1-7, (Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), a major metabolite of the pronociceptive neuropeptide Substance P (SP). SP is released in the spinal cord following a noxious stimulus and binds to the NK1 receptor. In contrast to SP, the degradation fragment SP1-7 is antinociceptive through binding to specific binding sites distinct from the NK1 receptor.
    [Show full text]
  • Role of Sigma-1 Receptor in Calcium Modulation: Possible Involvement in Cancer
    G C A T T A C G G C A T genes Review Role of Sigma-1 Receptor in Calcium Modulation: Possible Involvement in Cancer Ilaria Pontisso 1,2 and Laurent Combettes 1,2,* 1 UMR 1282, INSERM, Laboratoire de Biologie et Pharmacologie Appliquée, Ecole Normale Supérieure Paris Saclay, 91190 Gif Sur Yvette, France; [email protected] 2 Faculté des Sciences, Université Paris-Saclay, 91405 Orsay, France * Correspondence: [email protected] Abstract: Ca2+ signaling plays a pivotal role in the control of cellular homeostasis and aberrant regulation of Ca2+ fluxes have a strong impact on cellular functioning. As a consequence of this ubiquitous role, Ca2+ signaling dysregulation is involved in the pathophysiology of multiple diseases including cancer. Indeed, multiple studies have highlighted the role of Ca2+ fluxes in all the steps of cancer progression. In particular, the transfer of Ca2+ at the ER-mitochondrial contact sites, also known as mitochondrial associated membranes (MAMs), has been shown to be crucial for cancer cell survival. One of the proteins enriched at this site is the sigma-1 receptor (S1R), a protein that has been described as a Ca2+-sensitive chaperone that exerts a protective function in cells in various ways, including the modulation of Ca2+ signaling. Interestingly, S1R is overexpressed in many types of cancer even though the exact mechanisms by which it promotes cell survival are not fully elucidated. This review summarizes the findings describing the roles of S1R in the control of Ca2+ signaling and its involvement in cancer progression. Keywords: Ca2+ signalling; sigma-1 receptor; cancer Citation: Pontisso, I.; Combettes, L.
    [Show full text]
  • 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 molpharm.aspetjournals.org endoplasmic reticulum and plasma membranes with broad functions the pharmacology and mechanism(s) of action of the S1R. A 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.
    [Show full text]