Haloperidol is an antipsychotic agent that primarily acts as an antagonist of D2 dopamine receptors. Besides other receptor systems, it targets sigma 1 receptors (σ1Rs) and inositol 1,4,5-trisphosphate receptors (IP3Rs). Aim of this work was to investigate possible changes in IP3Rs and σ1Rs resulting from haloperidol treatment and to propose physiological consequences in differentiated NG-108 cells, i.e., effect on cellular plasticity. Haloperidol treatment resulted in up-regulation of both type 1 IP3Rs (IP3R1s) and σ1Rs at mRNA and protein levels. Haloperidol treatment did not alter expression of other types of IP3Rs. Calcium release from endoplasmic reticulum (ER) mediated by increased amount of IP3R1s elevated cytosolic calcium and generated ER stress. IP3R1s were bound to σ1Rs, and translocation of this complex from ER to nucleus occurred in the group of cells treated with haloperidol, which was followed by increased nuclear calcium levels. Haloperidol-induced changes in cytosolic, reticular, and nuclear calcium levels were similar when specific σ1 blocker -BD 1047- was used. Changes in calcium levels in nucleus, ER, and cytoplasm might be responsible for alterations in cellular plasticity, because length of neurites increased and number of neurites decreased in haloperidol-treated differentiated NG-108 cells.

Clinics of Pneumology and Phthisiology Jessenius Faculty of Medicine Martin Slovakia

Department of Physiology Faculty of Medicine Masaryk University Brno Czech Republic

Institute of Clinical and Translational Research Biomedical Research Center Slovak Academy of Sciences Dubravska cesta 9 84505 Bratislava Slovakia

Institute of Virology Biomedical Research Center Slovak Academy of Sciences Bratislava Slovakia

Zobrazit více v PubMed

Abou-Lovergne A, Collado-Hilly M, Monnet FP, Koukoui O, Prigent S, Coquil JF, Dupont G, Combettes L (2011) Investigation of the role of sigma1-receptors in inositol 1,4,5-trisphosphate dependent calcium signaling in hepatocytes. Cell Calcium 50:62–72 PubMed

Beaulieu JM, Espinoza S, Gainetdinov RR (2015) Dopamine receptors—IUPHAR Review 13. Br J Pharmacol 172:1–23 PubMed PMC

Bucolo C, Drago F, Lin LR, Reddy VN (2006) Sigma receptor ligands protect human retinal cells against oxidative stress. NeuroReport 17:287–291 PubMed

Corrales E, Navarro A, Cuenca P, Campos D (2016) Candidate gene study reveals DRD1 and DRD2 as putative interacting risk factors for youth depression. Psychiatry Res 244:71–77 PubMed

Crottes D, Guizouarn H, Martin P, Borgese F, Soriani O (2013) The sigma-1 receptor: a regulator of cancer cell electrical plasticity? Front Physiol 4:175 PubMed PMC

Do W, Herrera C, Mighty J, Shumskaya M, Redenti SM, Sauane M (2013) Sigma 1 receptor plays a prominent role in IL-24-induced cancer-specific apoptosis. Biochem Biophys Res Commun 439:215–220 PubMed

Dumont M, Lemaire S (1991) Interaction of 1,3-di(2-[5-3H]tolyl) guanidine with sigma 2 binding sites in rat heart membrane preparations. Eur J Pharmacol 209:245–248 PubMed

Dun Y, Thangaraju M, Prasad P, Ganapathy V, Smith SB (2007) Prevention of excitotoxicity in primary retinal ganglion cells by (+)-pentazocine, a sigma receptor-1 specific ligand. Invest Ophthalmol Vis Sci 48:4785–4794 PubMed PMC

Ela C, Barg J, Vogel Z, Hasin Y, Eilam Y (1994) Sigma receptor ligands modulate contractility, Ca++ influx and beating rate in cultured cardiac myocytes. J Pharmacol Exp Ther 269:1300–1309 PubMed

Gasparre G, Abate C, Berardi F, Cassano G (2012) The sigma-1 receptor antagonist PB212 reduces the Ca2+-release through the inositol (1, 4, 5)-trisphosphate receptor in SK-N-SH cells. Eur J Pharmacol 684:59–63 PubMed

Hamprecht B (1977) Structural, electrophysiological, biochemical, and pharmacological properties of neuroblastoma-glioma cell hybrids in cell culture. Int Rev Cytol 49:99–170 PubMed

Hasbi A, Fan T, Alijaniaram M, Nguyen T, Perreault ML, O’Dowd BF, George SR (2009) Calcium signaling cascade links dopamine D1–D2 receptor heteromer to striatal BDNF production and neuronal growth. Proc Natl Acad Sci U S A 106:21377–21382 PubMed PMC

Hayashi T, Su TP (2001) Regulating ankyrin dynamics: roles of sigma-1 receptors. Proc Natl Acad Sci USA 98:491–496 PubMed PMC

Hayashi T, Su TP (2007) Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca2+ signaling and cell survival. Cell 131:596–610 PubMed

Ishima T, Hashimoto K (2012) Potentiation of nerve growth factor-induced neurite outgrowth in PC12 cells by ifenprodil: the role of sigma-1 and IP3 receptors. PLoS ONE 7:e37989 PubMed PMC

Ishima T, Fujita Y, Hashimoto K (2014) Interaction of new antidepressants with sigma-1 receptor chaperones and their potentiation of neurite outgrowth in PC12 cells. Eur J Pharmacol 727:167–173 PubMed

Katnik C, Guerrero WR, Pennypacker KR, Herrera Y, Cuevas J (2006) Sigma-1 receptor activation prevents intracellular calcium dysregulation in cortical neurons during in vitro ischemia. J Pharmacol Exp Ther 319:1355–1365 PubMed

Kimura Y, Fujita Y, Shibata K, Mori M, Yamashita T (2013) Sigma-1 receptor enhances neurite elongation of cerebellar granule neurons via TrkB signaling. PLoS ONE 8:e75760 PubMed PMC

Kiviluoto S, Vervliet T, Ivanova H, Decuypere JP, De Smedt H, Missiaen L, Bultynck G, Parys JB (2013) Regulation of inositol 1,4,5-trisphosphate receptors during endoplasmic reticulum stress. Biochim Biophys Acta 1833:1612–1624 PubMed

Kubickova J, Hudecova S, Csaderova L, Soltysova A, Lichvarova L, Lencesova L, Babula P, Krizanova O (2016) Slow sulfide donor GYY4137 differentiates NG108-15 neuronal cells through different intracellular transporters than dbcAMP. Neuroscience 325:100–110 PubMed

Lencesova L, Hudecova S, Csaderova L, Markova J, Soltysova A, Pastorek M, Sedlak J, Wood ME, Whiteman M, Ondrias K, Krizanova O (2013) Sulphide signalling potentiates apoptosis through the up-regulation of IP3 receptor types 1 and 2. Acta Physiol (Oxf) 208:350–361 PubMed

Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275 PubMed

Markova J, Hudecova S, Soltysova A, Sirova M, Csaderova L, Lencesova L, Ondrias K, Krizanova O (2014) Sodium/calcium exchanger is upregulated by sulfide signaling, forms complex with the β1 and β3 but not β2 adrenergic receptors, and induces apoptosis. Pflugers Arch 466:1329–1342 PubMed

Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE (1976) The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther 197:517–532 PubMed

Martin PM, Ola MS, Agarwal N, Ganapathy V, Smith SB (2004) The sigma receptor ligand (+)-pentazocine prevents apoptotic retinal ganglion cell death induced in vitro by homocysteine and glutamate. Brain Res Mol Brain Res 123:66–75 PubMed PMC

Miki Y, Mori F, Kon T, Tanji K, Toyoshima Y, Yoshida M, Sasaki H, Kakita A, Takahashi H, Wakabayashi K (2014) Accumulation of the sigma-1 receptor is common to neuronal nuclear inclusions in various neurodegenerative diseases. Neuropathology 34:148–158 PubMed

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 PubMed

Mitsuda T, Omi T, Tanimukai H, Sakagami Y, Tagami S, Okochi M, Kudo T, Takeda M (2011) Sigma-1Rs are upregulated via PERK/eIF2α/ATF4 pathway and execute protective function in ER stress. Biochem Biophys Res Commun 415:519–525 PubMed

Mori T, Hayashi T, Hayashi E, Su TP (2013) Sigma-1 receptor chaperone at the ER-mitochondrion interface mediates the mitochondrion-ER-nucleus signaling for cellular survival. PLoS ONE 8:e76941 PubMed PMC

Novakova M, Ela C, Barg J, Vogel Z, Hasin Y, Eilam Y (1995) Inotropic action of sigma receptor ligands in isolated cardiac myocytes from adult rats. Eur J Pharmacol 286:19–30 PubMed

Novakova M, Bruderova V, Sulova Z, Kopacek J, Lacinova L, Kvetnansky R, Vasku A, Kaplan P, Krizanova O, Jurkovicova D (2007) Modulation of expression of the sigma receptors in the heart of rat and mouse in normal and pathological conditions. Gen Physiol Biophys 26:110–117 PubMed

Novakova M, Sedlakova B, Sirova M, Fialova K, Krizanova O (2010) Haloperidol increases expression of the inositol 1,4,5-trisphosphate receptors in rat cardiac atria, but not in ventricles. Gen Physiol Biophys 29:381–389 PubMed

Omi T, Tanimukai H, Kanayama D, Sakagami Y, Tagami S, Okochi M, Morihara T, Sato M, Yanagida K, Kitasyoji A, Hara H, Imaizumi K, Maurice T, Chevallier N, Marchal S, Takeda M, Kudo T (2014) Fluvoxamine alleviates ER stress via induction of sigma-1 receptor. Cell Death Dis 5:e1332 PubMed PMC

Ondrias K, Lencesova L, Sirova M, Labudova M, Pastorekova S, Kopacek J, Krizanova O (2011) Apoptosis induced clustering of IP(3)R1 in nuclei of non-differentiated PC12 cells. J Cell Physiol 226:3147–3155 PubMed

Rashid AJ, So CH, Kong MM, Furtak T, El-Ghundi M, Cheng R, O’Dowd BF, George SR (2007) D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum. Proc Natl Acad Sci USA 104:654–659 PubMed PMC

Remijnse PL, Eeckhout AM, van Guldener C (2002) Sudden death following a single oral administration of haloperidol. Ned Tijdschr Geneeskd 146:768–771 PubMed

Smith SB, Duplantier J, Dun Y, Mysona B, Roon P, Martin PM, Ganapathy V (2008) In vivo protection against retinal neurodegeneration by sigma receptor 1 ligand (+)-pentazocine. Invest Ophthamol Vis Sci 49:4154–4161 PubMed PMC

Spector DL (2006) SnapShot: cellular bodies. Cell 127(1070–1070):e1 PubMed

Su TP, Junien JL (1994) Sigma receptors in the central nervous system and the periphery. In: Itzhak Y (ed) Sigma receptors. Academic, London, pp 21–44

Tagashira H, Bhuiyan MS, Fukunaga K (2013) Diverse regulation of IP3 and ryanodine receptors by pentazocine through σ1-receptor in cardiomyocytes. Am J Physiol Heart Circ Physiol 305:1201–1212 PubMed

Tchedre KT, Yorio T (2008) Sigma-1 receptors protect RGC-5 cells from apoptosis by regulating intracellular calcium, Bax levels, and caspase-3 activation. Invest Ophthalmol Vis Sci 49:2577–2588 PubMed

Tchedre KT, Huang RQ, Dibas A, Krishnamoorthy RR, Dillon GH, Yorio T (2008) Sigma-1 receptor regulation of voltage-gated calcium channels involves a direct interaction. Invest Ophthalmol Vis Sci 49:4993–5002 PubMed

Wang L, Eldred JA, Sidaway P, Sanderson J, Smith AJ, Bowater RP, Reddan JR, Wormstone IM (2012) Sigma 1 receptor stimulation protects against oxidative damage through suppression of the ER stress responses in the human lens. Mech Ageing Dev 133:665–674 PubMed

Zhang XJ, Liu LL, Wu Y, Jiang SX, Zhong YM, Yang XL (2011) σ receptor 1 is preferentially involved in modulation of N-methyl-D-aspartate receptor-mediated light-evoked excitatory postsynaptic currents in rat retinal ganglion cells. Neurosignals 19:110–116 PubMed