Skip to main content

Advertisement

SpringerLink
Log in

Emerging Benefits: Pathophysiological Functions and Target Drugs of the Sigma-1 Receptor in Neurodegenerative Diseases

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The sigma-1 receptor (Sig-1R) is encoded by the SIGMAR1 gene and is a nonopioid transmembrane receptor located in the mitochondrial-associated endoplasmic reticulum membrane (MAM). It helps to locate endoplasmic reticulum calcium channels, regulates calcium homeostasis, and acts as a molecular chaperone to control cell fate and participate in signal transduction. It plays an important role in protecting neurons through a variety of signaling pathways and participates in the regulation of cognition and motor behavior closely related to neurodegenerative diseases. Based on its neuroprotective effects, Sig-1R has now become a breakthrough target for alleviating Alzheimer’s disease and other neurodegenerative diseases. This article reviews the most cutting-edge research on the function of Sig-1R under normal or pathologic conditions and target drugs of the sigma-1 receptor in neurodegenerative diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data Availability

Not applicable

Abbreviations

Sig-1R:

Sigma-1 receptor

MAM:

Mitochondrial-associated endoplasmic reticulum membrane

CHOP:

C/EBP homologous protein

DHEA:

Dehydroepiandrosterone

DHEAS:

DHEA sulfate

Znf179:

Zinc finger protein 179

ROS:

Reactive oxygen species

iNOS:

Inducible nitric oxide synthase

TNF-α:

Tumor necrosis factor-alpha

GSH:

Glutathione

Nrf2:

Erythroid-derived nuclear factor-related factor-2

HO-1:

Heme oxygenase-1

ERK1/2:

Extracellular signal-regulated kinase 1/2

GSK3β:

Glycogen synthase kinase 3β

NGF:

Nerve growth factor

TrkB:

Tropomyosin receptor kinase B

NMDAR:

N-methyl-D-aspartate receptors

HD:

Huntington’s disease

HTT:

Huntingtin gene

iPSC:

Induce pluripotent stem cells

AD:

Alzheimer’s disease

Aβ:

Amyloid β peptide

PD:

Parkinson’s disease

ALS:

Amyotrophic lateralizing sclerosis

GR:

Glucocorticoid receptor

dHMNs:

Distal hereditary motor neuropathy

RTT:

Rett syndrome

ONHAs:

Optic nerve head-derived astrocytes

PKC:

Protein kinase C

2-AG:

2-Arachidonic acid glyceride

ARF6:

ADP ribosylation factor

PKB:

Protein kinase B

eNOS:

Endothelial nitric oxide synthase

FTH1:

Ferritin heavy chain 1

TFR1:

Transferrin receptor protein 1

References

  1. Hayashi T, Su TP (2003) Sigma-1 receptors (sigma(1) binding sites) form raft-like microdomains and target lipid droplets on the endoplasmic reticulum: roles in endoplasmic reticulum lipid compartmentalization and export. J Pharmacol Exp Ther 306(2):718–725. https://doi.org/10.1124/jpet.103.051284

    Article  CAS  PubMed  Google Scholar 

  2. Ryskamp DA, Korban S, Zhemkov V, Kraskovskaya N, Bezprozvanny I (2019) Neuronal sigma-1 receptors: signaling functions and protective roles in neurodegenerative diseases. Front Neurosci 13:862. https://doi.org/10.3389/fnins.2019.00862

    Article  PubMed  PubMed Central  Google Scholar 

  3. Meunier J, Hayashi T (2010) Sigma-1 receptors regulate Bcl-2 expression by reactive oxygen species-dependent transcriptional regulation of nuclear factor kappaB. J Pharmacol Exp Ther 332(2):388–397. https://doi.org/10.1124/jpet.109.160960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Delprat B, Crouzier L, Su TP, Maurice T (2020) At the crossing of ER stress and MAMs: a key role of sigma-1 receptor? Adv Exp Med Biol 1131:699–718. https://doi.org/10.1007/978-3-030-12457-1_28

    Article  CAS  PubMed  Google Scholar 

  5. Al-Saif A, Al-Mohanna F, Bohlega S (2011) A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis. Ann Neurol 70(6):913–919. https://doi.org/10.1002/ana.22534

    Article  CAS  PubMed  Google Scholar 

  6. Feher A, Juhasz A, Laszlo A, Kalman J Jr, Pakaski M, Kalman J, Janka Z (2012) Association between a variant of the sigma-1 receptor gene and Alzheimer’s disease. Neurosci Lett 517(2):136–139. https://doi.org/10.1016/j.neulet.2012.04.046

    Article  CAS  PubMed  Google Scholar 

  7. Huang Y, Zheng L, Halliday G, Dobson-Stone C, Wang Y, Tang HD, Cao L, Deng YL et al. (2011) Genetic polymorphisms in sigma-1 receptor and apolipoprotein E interact to influence the severity of Alzheimer’s disease. Curr Alzheimer Res 8(7):765–770. https://doi.org/10.2174/156720511797633232

    Article  CAS  PubMed  Google Scholar 

  8. Ryskamp DA, Zhemkov V, Bezprozvanny I (2019) Mutational analysis of sigma-1 receptor’s role in synaptic stability. Front Neurosci 13:1012. https://doi.org/10.3389/fnins.2019.01012

    Article  PubMed  PubMed Central  Google Scholar 

  9. Alam S, Abdullah CS, Aishwarya R, Orr AW, Traylor J, Miriyala S, Panchatcharam M, Pattillo CB, et al. (2017) Sigmar1 regulates endoplasmic reticulum stress-induced C/EBP-homologous protein expression in cardiomyocyte. Biosci Rep 37(4):BSR20170898. https://doi.org/10.1042/BSR20170898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Manfredi G, Kawamata H (2017) Protein misfolding and mitochondrial dysfunction in amyotrophic lateral sclerosis. Protein folding disorders of the central nervous. pp 163–184. https://doi.org/10.1142/9789813222960_0007

  11. Shafiul Alam AWO, Pattillo CB, Shenuarin Bhuiyan Md (2016) Sigma-1 receptor dependent pathway for a protective endoplasmic reticulum stress response in cardiomyocytes. Circ Res 119:A281

    Google Scholar 

  12. Zhai M, Liu C, Li Y, Zhang P, Yu Z, Zhu H, Zhang L, Zhang Q, et al. (2019) Dexmedetomidine inhibits neuronal apoptosis by inducing Sigma-1 receptor signaling in cerebral ischemia-reperfusion injur. Aging 11(21):9556–9568. https://doi.org/10.18632/aging.102404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hayashi T (2019) The sigma-1 receptor in cellular stress signaling. Front Neurosci 13:733. https://doi.org/10.3389/fnins.2019.00733

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kaufmann WE, Sprouse J, Rebowe N, Hanania T, Klamer D, Missling CU (2019) ANAVEX(R)2–73 (blarcamesine), a sigma-1 receptor agonist, ameliorates neurologic impairments in a mouse model of Rett syndrome. Pharmacol Biochem Behav 187:172796. https://doi.org/10.1016/j.pbb.2019.172796

    Article  CAS  PubMed  Google Scholar 

  15. Tesei A, Cortesi M, Pignatta S, Arienti C, Dondio GM, Bigogno C, Malacrida A, Miloso M, et al. (2019) Anti-tumor efficacy assessment of the sigma receptor pan modulator RC-106. A promising therapeutic tool for pancreatic cancer. Front Pharmacol 10:490. https://doi.org/10.3389/fphar.2019.00490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bao Q, Zhao M, Chen L, Wang Y, Wu S, Wu W, Liu X (2017) MicroRNA-297 promotes cardiomyocyte hypertrophy via targeting sigma-1 receptor. Life Sci 175:1–10. https://doi.org/10.1016/j.lfs.2017.03.006

    Article  CAS  PubMed  Google Scholar 

  17. Schmidt HR, Betz RM, Dror RO, Kruse AC (2018) Structural basis for sigma1 receptor ligand recognition. Nat Struct Mol Biol 25(10):981–987. https://doi.org/10.1038/s41594-018-0137-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hayashi T, Su TP (2007) Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell 131(3):596–610. https://doi.org/10.1016/j.cell.2007.08.036

    Article  CAS  PubMed  Google Scholar 

  19. Watanabe S, Ilieva H, Tamada H, Nomura H, Komine O, Endo F, Jin S, Mancias P, et al. (2016) Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1- and SOD1-linked ALS. EMBO Mol Med 8(12):1421–1437. https://doi.org/10.15252/emmm.201606403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fukunaga YSHTK (2015) ALS-related SIGMAR1 missense mutation causes TDP-43 inclusion and mitochondrial injury. Biochem Mol Biol 29(S1). https://doi.org/10.1096/fasebj.29.1_supplement.564.3

  21. Couly S, Khalil B, Viguier V, Roussel J, Maurice T, Lievens JC (2020) Sigma-1 receptor is a key genetic modulator in amyotrophic lateral sclerosis. Hum Mol Genet 29(4):529–540. https://doi.org/10.1093/hmg/ddz267

    Article  CAS  PubMed  Google Scholar 

  22. Gutierrez T, Parra V, Troncoso R, Pennanen C, Contreras-Ferrat A, Vasquez-Trincado C, Morales PE, Lopez-Crisosto C, et al. (2014) Alteration in mitochondrial Ca(2+) uptake disrupts insulin signaling in hypertrophic cardiomyocytes. Cell Commun Signal 12:68. https://doi.org/10.1186/s12964-014-0068-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Krutetskaya ZI, Milenina LS, Antonov VG, Nozdrachev AD (2019) Sigma-1 receptor agonist amitriptyline inhibits store-dependent Ca(2+) entry in macrophages. Dokl Biochem Biophys 488(1):307–310. https://doi.org/10.1134/S1607672919050041

    Article  CAS  PubMed  Google Scholar 

  24. Cervero C, Blasco A, Tarabal O, Casanovas A, Piedrafita L, Navarro X, Esquerda JE, Caldero J (2018) Glial activation and central synapse loss, but not motoneuron degeneration, are prevented by the sigma-1 receptor agonist PRE-084 in the Smn2B/- mouse model of spinal muscular atrophy. J Neuropathol Exp Neurol 77(7):577–597. https://doi.org/10.1093/jnen/nly033

    Article  CAS  PubMed  Google Scholar 

  25. Zhao J, Mysona BA, Wang J, Gonsalvez GB, Smith SB, Bollinger KE (2017) Sigma 1 receptor regulates ERK activation and promotes survival of optic nerve head astrocytes. PLoS ONE 12(9):e0184421. https://doi.org/10.1371/journal.pone.0184421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang Y, Zhao CS (2019) Sigma-1 receptor activation ameliorates LPS-induced NO production and ROS formation through the Nrf2/HO-1 signaling pathway in cultured astrocytes. Neurosci Lett 711:134387. https://doi.org/10.1016/j.neulet.2019.134387

    Article  CAS  PubMed  Google Scholar 

  27. Su TC, Lin SH, Lee PT, Yeh SH, Hsieh TH, Chou SY, Su TP, Hung JJ, et al. (2016) The sigma-1 receptor-zinc finger protein 179 pathway protects against hydrogen peroxide-induced cell injury. Neuropharmacology 105:1–9. https://doi.org/10.1016/j.neuropharm.2016.01.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Choi SR, Roh DH, Yoon SY, Kang SY, Moon JY, Kwon SG, Choi HS, Han HJ, et al. (2013) Spinal sigma-1 receptors activate NADPH oxidase 2 leading to the induction of pain hypersensitivity in mice and mechanical allodynia in neuropathic rats. Pharmacol Res 74:56–67. https://doi.org/10.1016/j.phrs.2013.05.004

    Article  CAS  PubMed  Google Scholar 

  29. Almasi N, Torok S, Valkusz Z, Tajti M, Csonka A, Murlasits Z, Posa A, Varga C, et al. (2020) Sigma-1 receptor engages an anti-inflammatory and antioxidant feedback loop mediated by peroxiredoxin in experimental colitis. Antioxidants (Basel) 9(11):1081. https://doi.org/10.3390/antiox9111081

    Article  CAS  Google Scholar 

  30. Choi SR, Kwon SG, Choi HS, Han HJ, Beitz AJ, Lee JH (2016) Neuronal NOS activates spinal NADPH oxidase 2 contributing to central sigma-1 receptor-induced pain hypersensitivity in mice. Biol Pharm Bull 39(12):1922–1931. https://doi.org/10.1248/bpb.b16-00326

    Article  CAS  PubMed  Google Scholar 

  31. Lattard A, Poulen G, Bartolami S, Gerber YN, Perrin FE (2021) Negative impact of sigma-1 receptor agonist treatment on tissue integrity and motor function following spinal cord injury. Front Pharmacol 12:614949. https://doi.org/10.3389/fphar.2021.614949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pinho CM, Teixeira PF (1837) Glaser E (2014) Mitochondrial import and degradation of amyloid-beta peptide. Biochim Biophys Acta 7:1069–1074. https://doi.org/10.1016/j.bbabio.2014.02.007

    Article  CAS  Google Scholar 

  33. Goguadze N, Zhuravliova E, Morin D, Mikeladze D, Maurice T (2019) Sigma-1 receptor agonists induce oxidative stress in mitochondria and enhance complex I activity in physiological condition but protect against pathological oxidative stress. Neurotox Res 35(1):1–18. https://doi.org/10.1007/s12640-017-9838-2

    Article  CAS  PubMed  Google Scholar 

  34. Christ MG, Huesmann H, Nagel H, Kern A, Behl C (2019) Sigma-1 receptor activation induces autophagy and increases proteostasis capacity in vitro and in vivo. Cells 8(3):211. https://doi.org/10.3390/cells8030211

    Article  CAS  PubMed Central  Google Scholar 

  35. Mannack L (2015) The roles of Atg4-dependent LC3B delipidation, SigmaR1 and Climp-63 during mammalian autophagy. ETHOS. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.684363

  36. Yang H, Shen H, Li J, Guo LW (2019) SIGMAR1/Sigma-1 receptor ablation impairs autophagosome clearance. Autophagy 15(9):1539–1557. https://doi.org/10.1080/15548627.2019.1586248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Motawe ZY, Farsaei F, Abdelmaboud SS, Cuevas J, Breslin JW (2020) Sigma-1 receptor activation-induced glycolytic ATP production and endothelial barrier enhancement. Microcirculation 27(6):e12620. https://doi.org/10.1111/micc.12620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhang Y, Zhang X, Wei Q, Leng S, Li C, Han B, Bai Y, Zhang H, et al. (2020) Activation of sigma-1 receptor enhanced pericyte survival via the interplay between apoptosis and autophagy: implications for blood-brain barrier integrity in stroke. Transl Stroke Res 11(2):267–287. https://doi.org/10.1007/s12975-019-00711-0

    Article  CAS  PubMed  Google Scholar 

  39. Gutierrez T, Simmen T (2018) Endoplasmic reticulum chaperones tweak the mitochondrial calcium rheostat to control metabolism and cell death. Cell Calcium 70:64–75. https://doi.org/10.1016/j.ceca.2017.05.015

    Article  CAS  PubMed  Google Scholar 

  40. Jercic L, Kostic S, Vitlov Uljevic M, Vukusic Pusic T, Vukojevic K, Filipovic N (2019) Sigma-1 receptor expression in DRG neurons during a carrageenan-provoked inflammation. Anat Rec (Hoboken) 302(9):1620–1627. https://doi.org/10.1002/ar.24061

    Article  CAS  Google Scholar 

  41. Szabo A, Kovacs A, Frecska E, Rajnavolgyi E (2014) Psychedelic N, N-dimethyltryptamine and 5-methoxy-N, N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells. PLoS ONE 9(8):e106533. https://doi.org/10.1371/journal.pone.0106533

    Article  PubMed  PubMed Central  Google Scholar 

  42. Rosen DA, Seki SM, Fernandez-Castaneda A, Beiter RM, Eccles JD, Woodfolk JA, Gaultier A (2019) Modulation of the sigma-1 receptor-IRE1 pathway is beneficial in preclinical models of inflammation and sepsis. Sci Transl Med 11(478):eaau5266. https://doi.org/10.1126/scitranslmed.aau5266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rajnavolgyi ASAKEFE (2014) Activation of the sigma-1 receptor by specific ligands inhibits human inflammatory dendritic cell functions and effector T-lymphocyte responses. Paper presented at the Alzheimer’s Association International Conference

  44. Wu Z, Li L, Zheng LT, Xu Z, Guo L, Zhen X (2015) Allosteric modulation of sigma-1 receptors by SKF83959 inhibits microglia-mediated inflammation. J Neurochem 134(5):904–914. https://doi.org/10.1111/jnc.13182

    Article  CAS  PubMed  Google Scholar 

  45. Tsai SY, Pokrass MJ, Klauer NR, De Credico NE, Su TP (2014) Sigma-1 receptor chaperones in neurodegenerative and psychiatric disorders. Expert Opin Ther Targets 18(12):1461–1476. https://doi.org/10.1517/14728222.2014.972939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. van Waarde A, Ramakrishnan NK, Rybczynska AA, Elsinga PH, Ishiwata K, Nijholt IM, Luiten PG, Dierckx RA (2011) The cholinergic system, sigma-1 receptors and cognition. Behav Brain Res 221(2):543–554. https://doi.org/10.1016/j.bbr.2009.12.043

    Article  CAS  PubMed  Google Scholar 

  47. Wang Y, Jiang HF, Ni J, Guo L (2019) Pharmacological stimulation of sigma-1 receptor promotes activation of astrocyte via ERK1/2 and GSK3beta signaling pathway. Naunyn Schmiedebergs Arch Pharmacol 392(7):801–812. https://doi.org/10.1007/s00210-019-01632-3

    Article  CAS  PubMed  Google Scholar 

  48. Ruscher K, Wieloch T (2015) The involvement of the sigma-1 receptor in neurodegeneration and neurorestoration. J Pharmacol Sci 127(1):30–35. https://doi.org/10.1016/j.jphs.2014.11.011

    Article  CAS  PubMed  Google Scholar 

  49. Crouzier L, Couly S, Roques C, Peter C, Belkhiter R, Arguel Jacquemin M, Bonetto A, Delprat B, et al. (2020) Sigma-1 (sigma1) receptor activity is necessary for physiological brain plasticity in mice. Eur Neuropsychopharmacol 39:29–45. https://doi.org/10.1016/j.euroneuro.2020.08.010

    Article  CAS  PubMed  Google Scholar 

  50. Xu Q, Ji XF, Chi TY, Liu P, Jin G, Chen L, Zou LB (2017) Sigma-1 receptor in brain ischemia/reperfusion: possible role in the NR2A-induced pathway to regulate brain-derived neurotrophic factor. J Neurol Sci 376:166–175. https://doi.org/10.1016/j.jns.2017.03.027

    Article  CAS  PubMed  Google Scholar 

  51. Xu Q, Ji XF, Chi TY, Liu P, Jin G, Gu SL, Zou LB (2015) Sigma 1 receptor activation regulates brain-derived neurotrophic factor through NR2A-CaMKIV-TORC1 pathway to rescue the impairment of learning and memory induced by brain ischaemia/reperfusion. Psychopharmacology 232(10):1779–1791. https://doi.org/10.1007/s00213-014-3809-6

    Article  CAS  PubMed  Google Scholar 

  52. Liu DY, Chi TY, Ji XF, Liu P, Qi XX, Zhu L, Wang ZQ, Li L, et al. (2018) Sigma-1 receptor activation alleviates blood-brain barrier dysfunction in vascular dementia mice. Exp Neurol 308:90–99. https://doi.org/10.1016/j.expneurol.2018.07.002

    Article  CAS  PubMed  Google Scholar 

  53. Ruscher K, Shamloo M, Rickhag M, Ladunga I, Soriano L, Gisselsson L, Toresson H, Ruslim-Litrus L, et al. (2011) The sigma-1 receptor enhances brain plasticity and functional recovery after experimental stroke. Brain 134(Pt 3):732–746. https://doi.org/10.1093/brain/awq367

    Article  PubMed  Google Scholar 

  54. Shi JJ, Jiang QH, Zhang TN, Sun H, Shi WW, Gunosewoyo H, Yang F, Tang J, et al (2021) Sigma-1 receptor agonist TS-157 improves motor functional recovery by promoting neurite outgrowth and pERK in rats with focal cerebral ischemia. Molecules 26(5). https://doi.org/10.3390/molecules26051212

  55. Sanchez-Blazquez P, Pozo-Rodrigalvarez A, Merlos M, Garzon J (2018) The sigma-1 receptor antagonist, S1RA, reduces stroke damage, ameliorates post-stroke neurological deficits and suppresses the overexpression of MMP-9. Mol Neurobiol 55(6):4940–4951. https://doi.org/10.1007/s12035-017-0697-x

    Article  CAS  PubMed  Google Scholar 

  56. Ji LL, Peng JB, Fu CH, Tong L, Wang ZY (2017) Sigma-1 receptor activation ameliorates anxiety-like behavior through NR2A-CREB-BDNF signaling pathway in a rat model submitted to single-prolonged stress. Mol Med Rep 16(4):4987–4993. https://doi.org/10.3892/mmr.2017.7185

    Article  CAS  PubMed  Google Scholar 

  57. Fujimoto M, Hayashi T, Urfer R, Mita S, Su TP (2012) Sigma-1 receptor chaperones regulate the secretion of brain-derived neurotrophic factor. Synapse 66(7):630–639. https://doi.org/10.1002/syn.21549

    Article  CAS  PubMed  Google Scholar 

  58. Yamaguchi K, Shioda N, Yabuki Y, Zhang C, Han F, Fukunaga K (2018) SA4503, A potent sigma-1 receptor ligand, ameliorates synaptic abnormalities and cognitive dysfunction in a mouse model of ATR-X syndrome. Int J Mol Sci 19(9):2811. https://doi.org/10.3390/ijms19092811

    Article  CAS  PubMed Central  Google Scholar 

  59. Matsushima Y, Terada K, Kamei C, Sugimoto Y (2019) Sertraline inhibits nerve growth factor-induced neurite outgrowth in PC12 cells via a mechanism involving the sigma-1 receptor. Eur J Pharmacol 853:129–135. https://doi.org/10.1016/j.ejphar.2019.03.032

    Article  CAS  PubMed  Google Scholar 

  60. Ciesielski J, Su TP, Tsai SY (2016) Myristic acid hitchhiking on sigma-1 receptor to fend off neurodegeneration. Receptors Clin Investig 3(1):e1114. https://doi.org/10.14800/rci.1114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Brailoiu E, Chakraborty S, Brailoiu GC, Zhao P, Barr JL, Ilies MA, Unterwald EM, Abood ME, et al. (2019) Choline is an intracellular messenger linking extracellular stimuli to IP3-Evoked Ca(2+) signals through sigma-1 receptors. Cell Rep 26(2):330-337 e334. https://doi.org/10.1016/j.celrep.2018.12.051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Morihara R, Yamashita T, Liu X, Nakano Y, Fukui Y, Sato K, Ohta Y, Hishikawa N, et al. (2018) Protective effect of a novel sigma-1 receptor agonist is associated with reduced endoplasmic reticulum stress in stroke male mice. J Neurosci Res 96(10):1707–1716. https://doi.org/10.1002/jnr.24270

    Article  CAS  PubMed  Google Scholar 

  63. Zhao X, Zhu L, Liu D, Chi T, Ji X, Liu P, Yang X, Tian X, et sl. (2019) Sigma-1 receptor protects against endoplasmic reticulum stress-mediated apoptosis in mice with cerebral ischemia/reperfusion injury. Apoptosis 24(1–2):157–167. https://doi.org/10.1007/s10495-018-1495-2

    Article  PubMed  Google Scholar 

  64. Wang J, Saul A, Smith SB (2019) Activation of sigma 1 receptor extends survival of cones and improves visual acuity in a murine model of retinitis pigmentosa. Invest Ophthalmol Vis Sci 60(13):4397–4407. https://doi.org/10.1167/iovs.19-27709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bernard-Marissal N, Medard JJ, Azzedine H, Chrast R (2015) Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration. Brain 138(Pt 4):875–890. https://doi.org/10.1093/brain/awv008

    Article  PubMed  Google Scholar 

  66. Mavlyutov TA, Epstein ML, Andersen KA, Ziskind-Conhaim L, Ruoho AE (2010) The sigma-1 receptor is enriched in postsynaptic sites of C-terminals in mouse motoneurons An anatomical and behavioral study. Neuroscience 167(2):247–255. https://doi.org/10.1016/j.neuroscience.2010.02.022

    Article  CAS  PubMed  Google Scholar 

  67. Yang K, Wang C, Sun T (2019) The roles of intracellular chaperone proteins, sigma receptors, in Parkinson’s disease (PD) and major depressive disorder (MDD). Front Pharmacol 10:528. https://doi.org/10.3389/fphar.2019.00528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Abraham MJ, Fleming KL, Raymond S, Wong AYC, Bergeron R (2019) The sigma-1 receptor behaves as an atypical auxiliary subunit to modulate the functional characteristics of Kv1.2 channels expressed in HEK293 cells. Physiol Rep 7(12):e14147. https://doi.org/10.14814/phy2.14147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Krutetskaya ZI, Melnitskaya AV, Antonov VG, Nozdrachev AD (2019) Sigma-1 receptor antagonists haloperidol and chlorpromazine modulate the effect of glutoxim on Na(+) transport in frog skin. Dokl Biochem Biophys 484(1):63–65. https://doi.org/10.1134/S1607672919010186

    Article  CAS  PubMed  Google Scholar 

  70. Eddings CR, Arbez N, Akimov S, Geva M, Hayden MR, Ross CA (2019) Pridopidine protects neurons from mutant-huntingtin toxicity via the sigma-1 receptor. Neurobiol Dis 129:118–129. https://doi.org/10.1016/j.nbd.2019.05.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Francardo V, Geva M, Bez F, Denis Q, Steiner L, Hayden MR, Cenci MA (2019) Pridopidine induces functional neurorestoration via the sigma-1 receptor in a mouse model of Parkinson’s disease. Neurotherapeutics 16(2):465–479. https://doi.org/10.1007/s13311-018-00699-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Smith-Dijak AI, Nassrallah WB, Zhang LYJ, Geva M, Hayden MR, Raymond LA (2019) Impairment and restoration of homeostatic plasticity in cultured cortical neurons from a mouse model of huntington disease. Front Cell Neurosci 13:209. https://doi.org/10.3389/fncel.2019.00209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ryskamp D, Wu J, Geva M, Kusko R, Grossman I, Hayden M, Bezprozvanny I (2017) The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease. Neurobiol Dis 97(Pt A):46–59. https://doi.org/10.1016/j.nbd.2016.10.006

    Article  CAS  PubMed  Google Scholar 

  74. Iwamoto M, Nakamura Y, Takemura M, Hisaoka-Nakashima K, Morioka N (2020) TLR4-TAK1-p38 MAPK pathway and HDAC6 regulate the expression of sigma-1 receptors in rat primary cultured microglia. J Pharmacol Sci 144(1):23–29. https://doi.org/10.1016/j.jphs.2020.06.007

    Article  CAS  PubMed  Google Scholar 

  75. Ryskamp D, Wu L, Wu J, Kim D, Rammes G, Geva M, Hayden M, Bezprozvanny I (2019) Pridopidine stabilizes mushroom spines in mouse models of Alzheimer’s disease by acting on the sigma-1 receptor. Neurobiol Dis 124:489–504. https://doi.org/10.1016/j.nbd.2018.12.022

    Article  CAS  PubMed  Google Scholar 

  76. Maurice T, Volle JN, Strehaiano M, Crouzier L, Pereira C, Kaloyanov N, Virieux D, Pirat JL (2019) Neuroprotection in non-transgenic and transgenic mouse models of Alzheimer’s disease by positive modulation of sigma1 receptors. Pharmacol Res 144:315–330. https://doi.org/10.1016/j.phrs.2019.04.026

    Article  CAS  PubMed  Google Scholar 

  77. Kim WS, Fu Y, Dobson-Stone C, Hsiao JT, Shang K, Hallupp M, Schofield PR, Garner B, et al. (2018) Effect of fluvoxamine on amyloid-beta peptide generation and memory. J Alzheimers Dis 62(4):1777–1787. https://doi.org/10.3233/JAD-171001

    Article  CAS  PubMed  Google Scholar 

  78. Tsai SY, Pokrass MJ, Klauer NR, Nohara H, Su TP (2015) Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid. Proc Natl Acad Sci USA 112(21):6742–6747. https://doi.org/10.1073/pnas.1422001112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Tanji K, Miki Y, Maruyama A, Mimura J, Matsumiya T, Mori F, Imaizumi T, Itoh K, et al. (2015) Trehalose intake induces chaperone molecules along with autophagy in a mouse model of Lewy body disease. Biochem Biophys Res Commun 465(4):746–752. https://doi.org/10.1016/j.bbrc.2015.08.076

    Article  CAS  PubMed  Google Scholar 

  80. Voronin MV, Kadnikov IA, Voronkov DN, Seredenin SB (2019) Chaperone Sigma1R mediates the neuroprotective action of afobazole in the 6-OHDA model of Parkinson’s disease. Sci Rep 9(1):17020. https://doi.org/10.1038/s41598-019-53413-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kadnikov IA, Verbovaya ER, Voronkov DN, Voronin MV, Seredenin SB (2020) Deferred administration of afobazole induces Sigma1R-dependent restoration of striatal dopamine content in a mouse model of Parkinson’s disease. Int J Mol Sci 21(20):7620. https://doi.org/10.3390/ijms21207620

    Article  CAS  PubMed Central  Google Scholar 

  82. Francardo V, Bez F, Wieloch T, Nissbrandt H, Ruscher K, Cenci MA (2014) Pharmacological stimulation of sigma-1 receptors has neurorestorative effects in experimental parkinsonism. Brain 137(Pt 7):1998–2014. https://doi.org/10.1093/brain/awu107

    Article  PubMed  Google Scholar 

  83. Wang M, Wan C, He T, Han C, Zhu K, Waddington JL, Zhen X (2020) Sigma-1 receptor regulates mitophagy in dopaminergic neurons and contributes to dopaminergic protection. Neuropharmacology:108360. https://doi.org/10.1016/j.neuropharm.2020.108360

  84. Sun Y, Sukumaran P, Singh BB (2020) Sigma1 receptor inhibits TRPC1-mediated Ca(2+) entry that promotes dopaminergic cell death. Cell Mol Neurobiol. https://doi.org/10.1007/s10571-020-00892-5

    Article  PubMed  Google Scholar 

  85. Ionescu A, Gradus T, Altman T, Maimon R, Saraf Avraham N, Geva M, Hayden M, Perlson E (2019) Targeting the sigma-1 receptor via pridopidine ameliorates central features of ALS pathology in a SOD1(G93A) model. Cell Death Dis 10(3):210. https://doi.org/10.1038/s41419-019-1451-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Mavlyutov TA, Guo LW, Epstein ML, Ruoho AE (2015) Role of the sigma-1 receptor in amyotrophic lateral sclerosis (ALS). J Pharmacol Sci 127(1):10–16. https://doi.org/10.1016/j.jphs.2014.12.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Shinoda Y, Haga Y, Akagawa K, Fukunaga K (2020) Wildtype sigma1 receptor and the receptor agonist improve ALS-associated mutation-induced insolubility and toxicity. J Biol Chem 295(51):17573–17587. https://doi.org/10.1074/jbc.RA120.015012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zhang B, Wang L, Chen T, Hong J, Sha S, Wang J, Xiao H, Chen L (2017) Sigma-1 receptor deficiency reduces GABAergic inhibition in the basolateral amygdala leading to LTD impairment and depressive-like behaviors. Neuropharmacology 116:387–398. https://doi.org/10.1016/j.neuropharm.2017.01.014

    Article  CAS  PubMed  Google Scholar 

  89. Di T, Zhang S, Hong J, Zhang T, Chen L (2017) Hyperactivity of hypothalamic-pituitary-adrenal axis due to dysfunction of the hypothalamic glucocorticoid receptor in Sigma-1 receptor knockout mice. Front Mol Neurosci 10:287. https://doi.org/10.3389/fnmol.2017.00287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wang Y, Ni J, Gao T, Gao C, Guo L, Yin X (2020) Activation of astrocytic sigma-1 receptor exerts antidepressant-like effect via facilitating CD38-driven mitochondria transfer. Glia 68(11):2415–2426. https://doi.org/10.1002/glia.23850

    Article  PubMed  Google Scholar 

  91. Sanchez-Blazquez P, Cortes-Montero E, Rodriguez-Munoz M, Garzon J (2018) Sigma 1 receptor antagonists inhibit manic-like behaviors in two congenital strains of mice. Int J Neuropsychopharmacol 21(10):938–948. https://doi.org/10.1093/ijnp/pyy049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Liu X, Qu C, Shi S, Ye T, Wang L, Liu S, Zhang C, Liang J, et al. (2019) The reversal effect of sigma-1 receptor (S1R) agonist, SA4503, on atrial fibrillation after depression and its underlying mechanism. Front Physiol 10:1346. https://doi.org/10.3389/fphys.2019.01346

    Article  PubMed  PubMed Central  Google Scholar 

  93. Voronin MV, Kadnikov IA (2016) Contribution of sigma-1 receptor to cytoprotective effect of afobazole. Pharmacol Res Perspect 4(6):e00273. https://doi.org/10.1002/prp2.273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Liu X, Qu C, Yang H, Shi S, Zhang C, Zhang Y, Liang J, Yang B (2018) Chronic stimulation of the sigma-1 receptor ameliorates autonomic nerve dysfunction and atrial fibrillation susceptibility in a rat model of depression. Am J Physiol Heart Circ Physiol 315(6):H1521–H1531. https://doi.org/10.1152/ajpheart.00607.2017

    Article  CAS  PubMed  Google Scholar 

  95. Chen X, Zhang C, Guo Y, Liu X, Ye T, Fo Y, Qu C, Liang J, et al. (2020) Chronic stimulation of the sigma-1 receptor ameliorates ventricular ionic and structural remodeling in a rodent model of depression. Life Sci 257:118047. https://doi.org/10.1016/j.lfs.2020.118047

    Article  CAS  PubMed  Google Scholar 

  96. Fo Y, Zhang C, Chen X, Liu X, Ye T, Guo Y, Qu C, Shi S, Et al. (2020) Chronic sigma-1 receptor activation ameliorates ventricular remodeling and decreases susceptibility to ventricular arrhythmias after myocardial infarction in rats. Eur J Pharmacol 889:173614. https://doi.org/10.1016/j.ejphar.2020.173614

    Article  CAS  PubMed  Google Scholar 

  97. Qu J, Li M, Li D, Xin Y, Li J, Lei S, Wu W, Liu X (2021) Stimulation of sigma-1 receptor protects against cardiac fibrosis by alleviating IRE1 pathway and autophagy impairment. Oxid Med Cell Longev 2021:8836818. https://doi.org/10.1155/2021/8836818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ye T, Liu X, Qu C, Zhang C, Fo Y, Guo Y, Chen X, Shi S, et al. (2019) Chronic inhibition of the sigma-1 receptor exacerbates atrial fibrillation susceptibility in rats by promoting atrial remodeling. Life Sci 235:116837. https://doi.org/10.1016/j.lfs.2019.116837

    Article  CAS  PubMed  Google Scholar 

  99. Hashimoto K (2013) Sigma-1 receptor chaperone and brain-derived neurotrophic factor: emerging links between cardiovascular disease and depression. Prog Neurobiol 100:15–29. https://doi.org/10.1016/j.pneurobio.2012.09.001

    Article  CAS  PubMed  Google Scholar 

  100. Lenart L, Hodrea J, Hosszu A, Koszegi S, Zelena D, Balogh D, Szkibinszkij E, Veres-Szekely A, et al. (2016) The role of sigma-1 receptor and brain-derived neurotrophic factor in the development of diabetes and comorbid depression in streptozotocin-induced diabetic rats. Psychopharmacology 233(7):1269–1278. https://doi.org/10.1007/s00213-016-4209-x

    Article  CAS  PubMed  Google Scholar 

  101. Yagasaki Y, Numakawa T, Kumamaru E, Hayashi T, Su TP, Kunugi H (2006) Chronic antidepressants potentiate via sigma-1 receptors the brain-derived neurotrophic factor-induced signaling for glutamate release. J Biol Chem 281(18):12941–12949. https://doi.org/10.1074/jbc.M508157200

    Article  CAS  PubMed  Google Scholar 

  102. Luty AA, Kwok JB, Dobson-Stone C, Loy CT, Coupland KG, Karlstrom H, Sobow T, Tchorzewska J, et al. (2010) Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease. Ann Neurol 68(5):639–649. https://doi.org/10.1002/ana.22274

    Article  CAS  PubMed  Google Scholar 

  103. Hindmarch I, Hashimoto K (2010) Cognition and depression: the effects of fluvoxamine, a sigma-1 receptor agonist, reconsidered. Hum Psychopharmacol 25(3):193–200. https://doi.org/10.1002/hup.1106

    Article  CAS  PubMed  Google Scholar 

  104. Ishikawa MHK (2010) (2010) The role of sigma-1 receptors in the pathophysiology of neuropsychiatric diseases. J Recept Ligand Channel Res 3:25–36. https://doi.org/10.2147/JRLCR.S8453

    Article  CAS  Google Scholar 

  105. Li D, Zhang SZ, Yao YH, Xiang Y, Ma XY, Wei XL, Yan HT, Liu XY (2017) Sigma-1 receptor agonist increases axon outgrowth of hippocampal neurons via voltage-gated calcium ions channels. CNS Neurosci Ther 23(12):930–939. https://doi.org/10.1111/cns.12768

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Niitsu T, Iyo M, Hashimoto K (2012) Sigma-1 receptor agonists as therapeutic drugs for cognitive impairment in neuropsychiatric diseases. Curr Pharm Des 18(7):875–883. https://doi.org/10.2174/138161212799436476

    Article  CAS  PubMed  Google Scholar 

  107. Gregianin E, Pallafacchina G, Zanin S, Crippa V, Rusmini P, Poletti A, Fang M, Li Z, et al. (2016) Loss-of-function mutations in the SIGMAR1 gene cause distal hereditary motor neuropathy by impairing ER-mitochondria tethering and Ca2+ signalling. Hum Mol Genet 25(17):3741–3753. https://doi.org/10.1093/hmg/ddw220

    Article  CAS  PubMed  Google Scholar 

  108. Smith SB, Wang J, Cui X, Mysona BA, Zhao J, Bollinger KE (2018) Sigma 1 receptor: a novel therapeutic target in retinal disease. Prog Retin Eye Res 67:130–149. https://doi.org/10.1016/j.preteyeres.2018.07.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Mavlyutov TA, Nickells RW, Guo LW (2011) Accelerated retinal ganglion cell death in mice deficient in the Sigma-1 receptor. Mol Vis 17:1034–1043

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Ha Y, Saul A, Tawfik A, Williams C, Bollinger K, Smith R, Tachikawa M, Zorrilla E, et al. (2011) Late-onset inner retinal dysfunction in mice lacking sigma receptor 1 (sigmaR1). Invest Ophthalmol Vis Sci 52(10):7749–7760. https://doi.org/10.1167/iovs.11-8169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Wang J, Smith SB (2019) A novel mechanism of sigma 1 receptor neuroprotection: modulation of miR-214-3p. Adv Exp Med Biol 1185:463–467. https://doi.org/10.1007/978-3-030-27378-1_76

    Article  CAS  PubMed  Google Scholar 

  112. Wang J, Zhao J, Cui X, Mysona BA, Navneet S, Saul A, Ahuja M, Lambert N, et al. (2019) The molecular chaperone sigma 1 receptor mediates rescue of retinal cone photoreceptor cells via modulation of NRF2. Free Radic Biol Med 134:604–616. https://doi.org/10.1016/j.freeradbiomed.2019.02.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Ha Y, Dun Y, Thangaraju M, Duplantier J, Dong Z, Liu K, Ganapathy V, Smith SB (2011) Sigma receptor 1 modulates endoplasmic reticulum stress in retinal neurons. Invest Ophthalmol Vis Sci 52(1):527–540. https://doi.org/10.1167/iovs.10-5731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Mysona BA, Zhao J, Smith S, Bollinger KE (2018) Relationship between sigma-1 receptor and BDNF in the visual system. Exp Eye Res 167:25–30. https://doi.org/10.1016/j.exer.2017.10.012

    Article  CAS  PubMed  Google Scholar 

  115. Bravo-Caparros I, Ruiz-Cantero MC, Perazzoli G, Cronin SJF, Vela JM, Hamed MF, Penninger JM, Baeyens JM, et al. (2020) Sigma-1 receptors control neuropathic pain and macrophage infiltration into the dorsal root ganglion after peripheral nerve injury. FASEB J 34(4):5951–5966. https://doi.org/10.1096/fj.201901921R

    Article  CAS  PubMed  Google Scholar 

  116. Roh DH, Yoon SY, Seo HS, Kang SY, Moon JY, Song S, Beitz AJ, Lee JH (2010) Sigma-1 receptor-induced increase in murine spinal NR1 phosphorylation is mediated by the PKCalpha and epsilon, but not the PKCzeta, isoforms. Neurosci Lett 477(2):95–99. https://doi.org/10.1016/j.neulet.2010.04.041

    Article  CAS  PubMed  Google Scholar 

  117. Roh DH, Kim HW, Yoon SY, Seo HS, Kwon YB, Kim KW, Han HJ, Beitz AJ, et al. (2008) Intrathecal administration of sigma-1 receptor agonists facilitates nociception: involvement of a protein kinase C-dependent pathway. J Neurosci Res 86(16):3644–3654. https://doi.org/10.1002/jnr.21802

    Article  CAS  PubMed  Google Scholar 

  118. Cormaci G, Mori T, Hayashi T, Su TP (2007) Protein kinase A activation down-regulates, whereas extracellular signal-regulated kinase activation up-regulates sigma-1 receptors in B-104 cells: implication for neuroplasticity. J Pharmacol Exp Ther 320(1):202–210. https://doi.org/10.1124/jpet.106.108415

    Article  CAS  PubMed  Google Scholar 

  119. Merlos M, Romero L, Zamanillo D, Plata-Salaman C, Vela JM (2017) Sigma-1 receptor and pain. Handb Exp Pharmacol 244:131–161. https://doi.org/10.1007/164_2017_9

    Article  CAS  PubMed  Google Scholar 

  120. Shin SM, Wang F, Qiu C, Itson-Zoske B, Hogan QH, Yu H (2020) Sigma-1 receptor activity in primary sensory neurons is a critical driver of neuropathic pain. Gene Ther. https://doi.org/10.1038/s41434-020-0157-5

    Article  PubMed  Google Scholar 

  121. Carcole M, Zamanillo D, Merlos M, Fernandez-Pastor B, Cabanero D, Maldonado R (2019) Blockade of the sigma-1 receptor relieves Cognitive and emotional impairments associated to chronic osteoarthritis pain. Front Pharmacol 10:468. https://doi.org/10.3389/fphar.2019.00468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ruiz-Cantero MC, Gonzalez-Cano R, Tejada MA, Santos-Caballero M, Perazzoli G, Nieto FR, Cobos EJ (2021) Sigma-1 receptor: a drug target for the modulation of neuroimmune and neuroglial interactions during chronic pain. Pharmacol Res 163:105339. https://doi.org/10.1016/j.phrs.2020.105339

    Article  CAS  PubMed  Google Scholar 

  123. Sachau J, Bruckmueller H, Gierthmuhlen J, Magerl W, Kaehler M, Haenisch S, Binder A, Caliebe A, et al. (2019) SIGMA-1 receptor gene variants affect the somatosensory phenotype in neuropathic pain patients. J Pain 20(2):201–214. https://doi.org/10.1016/j.jpain.2018.08.011

    Article  CAS  PubMed  Google Scholar 

  124. Gris G, Portillo-Salido E, Aubel B, Darbaky Y, Deseure K, Vela JM, Merlos M, Zamanillo D (2016) The selective sigma-1 receptor antagonist E-52862 attenuates neuropathic pain of different aetiology in rats. Sci Rep 6:24591. https://doi.org/10.1038/srep24591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Montilla-Garcia A, Perazzoli G, Tejada MA, Gonzalez-Cano R, Sanchez-Fernandez C, Cobos EJ, Baeyens JM (2018) Modality-specific peripheral antinociceptive effects of mu-opioid agonists on heat and mechanical stimuli: contribution of sigma-1 receptors. Neuropharmacology 135:328–342. https://doi.org/10.1016/j.neuropharm.2018.03.025

    Article  CAS  PubMed  Google Scholar 

  126. Romero L, Merlos M, Vela JM (2016) Antinociception by sigma-1 receptor antagonists: central and peripheral effects. Adv Pharmacol 75:179–215. https://doi.org/10.1016/bs.apha.2015.11.003

    Article  CAS  PubMed  Google Scholar 

  127. Vidal-Torres A, Fernandez-Pastor B, Carceller A, Vela JM, Merlos M, Zamanillo D (2019) Supraspinal and peripheral, but not intrathecal, sigma1R blockade by S1RA enhances morphine antinociception. Front Pharmacol 10:422. https://doi.org/10.3389/fphar.2019.00422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Montilla-Garcia A, Tejada MA, Ruiz-Cantero MC, Bravo-Caparros I, Yeste S, Zamanillo D, Cobos EJ (2019) Modulation by sigma-1 receptor of morphine analgesia and tolerance: nociceptive pain, tactile allodynia and grip strength deficits during joint inflammation. Front Pharmacol 10:136. https://doi.org/10.3389/fphar.2019.00136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Mei J, Pasternak GW (2002) Sigma1 receptor modulation of opioid analgesia in the mouse. J Pharmacol Exp Ther 300(3):1070–1074. https://doi.org/10.1124/jpet.300.3.1070

    Article  CAS  PubMed  Google Scholar 

  130. Castany S, Codony X, Zamanillo D, Merlos M, Verdu E, Boadas-Vaello P (2019) Repeated sigma-1 receptor antagonist MR309 administration modulates central neuropathic pain development after spinal cord injury in mice. Front Pharmacol 10:222. https://doi.org/10.3389/fphar.2019.00222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Cirino TJ, Eans SO, Medina JM, Wilson LL, Mottinelli M, Intagliata S, McCurdy CR, McLaughlin JP (2019) Characterization of sigma 1 receptor antagonist CM-304 and its analog, AZ-66: novel therapeutics against allodynia and induced pain. Front Pharmacol 10:678. https://doi.org/10.3389/fphar.2019.00678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Nieto FR, Cendan CM, Sanchez-Fernandez C, Cobos EJ, Entrena JM, Tejada MA, Zamanillo D, Vela JM, et al. (2012) Role of sigma-1 receptors in paclitaxel-induced neuropathic pain in mice. J Pain 13(11):1107–1121. https://doi.org/10.1016/j.jpain.2012.08.006

    Article  CAS  PubMed  Google Scholar 

  133. Carcole M, Kummer S, Goncalves L, Zamanillo D, Merlos M, Dickenson AH, Fernandez-Pastor B, Cabanero D, et al. (2019) Sigma-1 receptor modulates neuroinflammation associated with mechanical hypersensitivity and opioid tolerance in a mouse model of osteoarthritis pain. Br J Pharmacol 176(20):3939–3955. https://doi.org/10.1111/bph.14794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Yamamoto G, Kamiya Y, Sasaki M, Ikoma M, Baba H, Kohno T (2019) Neurosteroid dehydroepiandrosterone sulphate enhances pain transmission in rat spinal cord dorsal horn. Br J Anaesth 123(2):e215–e225. https://doi.org/10.1016/j.bja.2019.03.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Choi SR, Roh DH, Yoon SY, Choi HS, Kang SY, Han HJ, Beitz AJ, Lee JH (2019) Spinal cytochrome P450c17 plays a key role in the development of neuropathic mechanical allodynia: involvement of astrocyte sigma-1 receptors. Neuropharmacology 149:169–180. https://doi.org/10.1016/j.neuropharm.2019.02.013

    Article  CAS  PubMed  Google Scholar 

  136. Wang X, Feng C, Qiao Y, Zhao X (2018) Sigma 1 receptor mediated HMGB1 expression in spinal cord is involved in the development of diabetic neuropathic pain. Neurosci Lett 668:164–168. https://doi.org/10.1016/j.neulet.2018.02.002

    Article  CAS  PubMed  Google Scholar 

  137. Wang SM, Goguadze N, Kimura Y, Yasui Y, Pan B, Wang TY, Nakamura Y, Lin YT, et al. (2021) Correction to: genomic action of sigma-1 receptor chaperone relates to neuropathic pain. Mol Neurobiol. https://doi.org/10.1007/s12035-021-02310-3

    Article  PubMed  PubMed Central  Google Scholar 

  138. Cottone P, Wang X, Park JW, Valenza M, Blasio A, Kwak J, Iyer MR, Steardo L, et al. (2012) Antagonism of sigma-1 receptors blocks compulsive-like eating. Neuropsychopharmacology 37(12):2593–2604. https://doi.org/10.1038/npp.2012.89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Sambo DO, Lin M, Owens A, Lebowitz JJ, Richardson B, Jagnarine DA, Shetty M, Rodriquez M, et al. (2017) The sigma-1 receptor modulates methamphetamine dysregulation of dopamine neurotransmission. Nat Commun 8(1):2228. https://doi.org/10.1038/s41467-017-02087-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Tahvilian R, Amini K, Zhaleh H (2019) Signal transduction of improving effects of ibudilast on methamphetamine induced cell death. Asian Pac J Cancer Prev 20(9):2763–2774. https://doi.org/10.31557/APJCP.2019.20.9.2763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Tapia MA, Lever JR, Lever SZ, Will MJ, Park ES, Miller DK (2019) Sigma-1 receptor ligand PD144418 and sigma-2 receptor ligand YUN-252 attenuate the stimulant effects of methamphetamine in mice. Psychopharmacology 236(11):3147–3158. https://doi.org/10.1007/s00213-019-05268-2

    Article  CAS  PubMed  Google Scholar 

  142. Prasad A, Kulkarni R, Shrivastava A, Jiang S, Lawson K, Groopman JE (2019) Methamphetamine functions as a novel CD4(+) T-cell activator via the sigma-1 receptor to enhance HIV-1 infection. Sci Rep 9(1):958. https://doi.org/10.1038/s41598-018-35757-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Tsai SY, Chuang JY, Tsai MS, Wang XF, Xi ZX, Hung JJ, Chang WC, Bonci A, et al. (2015) Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope. Proc Natl Acad Sci USA 112(47):E6562-6570. https://doi.org/10.1073/pnas.1518894112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Nakamura Y, Dryanovski DI, Kimura Y, Jackson SN, Woods AS, Yasui Y, Tsai SY, Patel S, et al. (2019) Cocaine-induced endocannabinoid signaling mediated by sigma-1 receptors and extracellular vesicle secretion. Elife 8:e47209. https://doi.org/10.7554/eLife.47209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Kourrich S, Hayashi T, Chuang JY, Tsai SY, Su TP, Bonci A (2013) Dynamic interaction between sigma-1 receptor and Kv1.2 shapes neuronal and behavioral responses to cocaine. Cell 152(1–2):236–247. https://doi.org/10.1016/j.cell.2012.12.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Barr JL, Deliu E, Brailoiu GC, Zhao P, Yan G, Abood ME, Unterwald EM, Brailoiu E (2015) Mechanisms of activation of nucleus accumbens neurons by cocaine via sigma-1 receptor-inositol 1,4,5-trisphosphate-transient receptor potential canonical channel pathways. Cell Calcium 58(2):196–207. https://doi.org/10.1016/j.ceca.2015.05.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Abdullah CS, Alam S, Aishwarya R, Miriyala S, Panchatcharam M, Bhuiyan MAN, Peretik JM, Orr AW, et al. (2018) Cardiac dysfunction in the sigma 1 receptor knockout mouse associated with impaired mitochondrial dynamics and bioenergetics. J Am Heart Assoc 7(20):e009775. https://doi.org/10.1161/JAHA.118.009775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Gao QJ, Yang B, Chen J, Shi SB, Yang HJ, Liu X (2018) Sigma-1 receptor stimulation with PRE-084 ameliorates myocardial ischemia-reperfusion injury in rats. Chin Med J (Engl) 131(5):539–543. https://doi.org/10.4103/0366-6999.226076

    Article  Google Scholar 

  149. Bai T, Lei P, Zhou H, Liang R, Zhu R, Wang W, Zhou L, Sun Y (2019) Sigma-1 receptor protects against ferroptosis in hepatocellular carcinoma cells. J Cell Mol Med 23(11):7349–7359. https://doi.org/10.1111/jcmm.14594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Gianluca Civenni MM, Pandit Shusil, De Monte C, Sereni F, Merulla J, Zadic S, Losa M, Allegrini S, et al. (2017) Sigma-1 receptor control tumorigenic and stem cell-like phenotype in human cancers. Am Assoc Cancer Res 77(13 Supplement):2900–2900. https://doi.org/10.1158/1538-7445.AM2017-2900

    Article  Google Scholar 

  151. Soriani O, Rapetti-Mauss R (2017) Sigma 1 receptor and ion channel dynamics in cancer. Adv Exp Med Biol 964:63–77. https://doi.org/10.1007/978-3-319-50174-1_6

    Article  CAS  PubMed  Google Scholar 

  152. Wu Y, Bai X, Li X, Zhu C, Wu ZP (2018) Overexpression of sigma-1 receptor in MCF-7 cells enhances proliferation via the classic protein kinase C subtype signaling pathway. Oncol Lett 16(5):6763–6769. https://doi.org/10.3892/ol.2018.9448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Spruce BA, Campbell LA, McTavish N, Cooper MA, Appleyard MV, O’Neill M, Howie J, Samson J, et al. (2004) Small molecule antagonists of the sigma-1 receptor cause selective release of the death program in tumor and self-reliant cells and inhibit tumor growth in vitro and in vivo. Cancer Res 64(14):4875–4886. https://doi.org/10.1158/0008-5472.CAN-03-3180

    Article  CAS  PubMed  Google Scholar 

  154. Su TP, Su TC, Nakamura Y, Tsai SY (2016) The sigma-1 receptor as a pluripotent modulator in living systems. Trends Pharmacol Sci 37(4):262–278. https://doi.org/10.1016/j.tips.2016.01.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Miki Y, Mori F, Kon T, Tanji K, Toyoshima Y, Yoshida M, Sasaki H, Kakita A, et al. (2014) Accumulation of the sigma-1 receptor is common to neuronal nuclear inclusions in various neurodegenerative diseases. Neuropathology 34(2):148–158. https://doi.org/10.1111/neup.12080

    Article  CAS  PubMed  Google Scholar 

  156. Miki Y, Tanji K, Mori F, Wakabayashi K (2015) Sigma-1 receptor is involved in degradation of intranuclear inclusions in a cellular model of Huntington’s disease. Neurobiol Dis 74:25–31. https://doi.org/10.1016/j.nbd.2014.11.005

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Chao Liu for her help in manuscript revision.

Funding

This work was supported by the National Natural Science Foundation of China (81870173), Young Talent Project of Hubei Provincial Health and Health Committee (WJ2019Q013), Scientific Research Plan of Hubei Provincial Department of Education (D20202803), Natural Science Foundation of Hubei Province (2020CFB851), and Hubei University of Science and Technology School-level Fund (No.2020XZ13, BK202009).

Author information

Author notes

  1. Ning-hua Wu and Yu Ye are equal contributors.

Authors and Affiliations

  1. Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, 437000, Hubei, China

    Ning-hua Wu, Yu Ye, Bin-bin Wan, Chao Liu & Qing-jie Chen

  2. Basic Medical College, Hubei University of Science and Technology, Xianning, 437000, Hubei, China

    Ning-hua Wu

  3. Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China

    Yuan-dong Yu

Authors
  1. Ning-hua Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bin-bin Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuan-dong Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qing-jie Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Ning-hua Wu and Yu Ye edited and wrote the manuscript. Bin-bin Wan and Yuan-dong Yu revised and participated in the discussion of the manuscript. Chao Liu and Qing-Jie Chen participated in the manuscript design and coordination. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Chao Liu or Qing-jie Chen.

Ethics declarations

Ethics Approval

Not applicable

Consent for Publication

All participants consent for the publication of this manuscript.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, Nh., Ye, Y., Wan, Bb. et al. Emerging Benefits: Pathophysiological Functions and Target Drugs of the Sigma-1 Receptor in Neurodegenerative Diseases. Mol Neurobiol 58, 5649–5666 (2021). https://doi.org/10.1007/s12035-021-02524-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-021-02524-5

Keywords

Search

Navigation