G protein-biased LPAR1 agonism of prototypic antidepressants: Implication in the identification of novel therapeutic target for depression.
Journal
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
ISSN: 1740-634X
Titre abrégé: Neuropsychopharmacology
Pays: England
ID NLM: 8904907
Informations de publication
Date de publication:
06 Sep 2023
06 Sep 2023
Historique:
received:
09
03
2023
accepted:
24
08
2023
revised:
01
08
2023
pubmed:
7
9
2023
medline:
7
9
2023
entrez:
6
9
2023
Statut:
aheadofprint
Résumé
Prototypic antidepressants, such as tricyclic/tetracyclic antidepressants (TCAs), have multiple pharmacological properties and have been considered to be more effective than newer antidepressants, such as selective serotonin reuptake inhibitors, in treating severe depression. However, the clinical contribution of non-monoaminergic effects of TCAs remains elusive. In this study, we discovered that amitriptyline, a typical TCA, directly binds to the lysophosphatidic acid receptor 1 (LPAR1), a G protein-coupled receptor, and activates downstream G protein signaling, while exerting a little effect on β-arrestin recruitment. This suggests that amitriptyline acts as a G protein-biased agonist of LPAR1. This biased agonism was specific to TCAs and was not observed with other antidepressants. LPAR1 was found to be involved in the behavioral effects of amitriptyline. Notably, long-term infusion of mouse hippocampus with the potent G protein-biased LPAR agonist OMPT, but not the non-biased agonist LPA, induced antidepressant-like behavior, indicating that G protein-biased agonism might be necessary for the antidepressant-like effects. Furthermore, RNA-seq analysis revealed that LPA and OMPT have opposite patterns of gene expression changes in the hippocampus. Pathway analysis indicated that long-term treatment with OMPT activated LPAR1 downstream signaling (Rho and MAPK), whereas LPA suppressed LPAR1 signaling. Our findings provide insights into the mechanisms underlying the non-monoaminergic antidepressant effects of TCAs and identify the G protein-biased agonism of LPAR1 as a promising target for the development of novel antidepressants.
Identifiants
pubmed: 37673966
doi: 10.1038/s41386-023-01727-9
pii: 10.1038/s41386-023-01727-9
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 18H02756
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 21K07501
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 21H04791 and 21H051130
Organisme : MEXT | Japan Science and Technology Agency (JST)
ID : PMJFR215T and JPMJMS2023
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : 21gm0010004h9905
Informations de copyright
© 2023. The Author(s).
Références
Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391:1357–66.
pubmed: 29477251
pmcid: 5889788
doi: 10.1016/S0140-6736(17)32802-7
Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. J Affect Disord. 2000;58:19–36.
pubmed: 10760555
doi: 10.1016/S0165-0327(99)00092-0
Kajitani N, Miyano K, Okada-Tsuchioka M, Abe H, Itagaki K, Hisaoka-Nakashima K, et al. Identification of lysophosphatidic acid receptor 1 in Astroglial Cells as a target for Glial cell line-derived neurotrophic factor expression induced by antidepressants. J Biol Chem. 2016;291:27364–70.
pubmed: 27864362
pmcid: 5207162
doi: 10.1074/jbc.M116.753871
Olianas MC, Dedoni S, Onali P. LPA1 mediates antidepressant-induced ERK1/2 signaling and protection from oxidative stress in glial cells. J Pharmacol Exp Ther. 2016;359:340–53.
pubmed: 27605627
doi: 10.1124/jpet.116.236455
Tokunaga N, Takimoto T, Nakamura Y, Hisaoka-Nakashima K, Morioka N. Downregulation of connexin 43 potentiates amitriptyline-induced brain-derived neurotrophic factor expression in primary astrocytes through lysophosphatidic acid receptor
pubmed: 35490723
doi: 10.1016/j.ejphar.2022.174986
Moreno-Fernandez RD, Tabbai S, Castilla-Ortega E, Perez-Martin M, Estivill-Torrus G, Rodriguez de Fonseca F, et al. Stress, depression, resilience and ageing: a role for the LPA-LPA1 pathway. Curr Neuropharmacol. 2018;16:271–83.
pubmed: 28699486
doi: 10.2174/1570159X15666170710200352
Moreno-Fernández RD, Pérez-Martín M, Castilla-Ortega E, Rosell Del Valle C, García-Fernández MI, Chun J, et al. maLPA1-null mice as an endophenotype of anxious depression. Transl Psychiatry. 2017;7:e1077.
pubmed: 28375206
pmcid: 5416683
doi: 10.1038/tp.2017.24
Rosell-Valle C, Martínez-Losa M, Matas-Rico E, Castilla-Ortega E, Zambrana-Infantes E, Gómez-Conde AI, et al. GABAergic deficits in absence of LPA
pubmed: 33792787
doi: 10.1007/s00429-021-02261-4
Yamada M, Tsukagoshi M, Hashimoto T, Oka J, Saitoh A. Lysophosphatidic acid induces anxiety-like behavior via its receptors in mice. J Neural Transm (Vienna). 2015;122:487–94.
pubmed: 25119538
doi: 10.1007/s00702-014-1289-9
Castilla-Ortega E, Escuredo L, Bilbao A, Pedraza C, Orio L, Estivill-Torrús G, et al. 1-Oleoyl lysophosphatidic acid: a new mediator of emotional behavior in rats. PLoS One. 2014;9:e85348.
pubmed: 24409327
pmcid: 3883702
doi: 10.1371/journal.pone.0085348
Urs NM, Jones KT, Salo PD, Severin JE, Trejo J, Radhakrishna H. A requirement for membrane cholesterol in the beta-arrestin- and clathrin-dependent endocytosis of LPA1 lysophosphatidic acid receptors. J Cell Sci. 2005;118:5291–304.
pubmed: 16263766
doi: 10.1242/jcs.02634
Zhou Y, Little PJ, Ta HT, Xu S, Kamato D. Lysophosphatidic acid and its receptors: pharmacology and therapeutic potential in atherosclerosis and vascular disease. Pharmacol Ther. 2019;204:107404.
pubmed: 31472182
doi: 10.1016/j.pharmthera.2019.107404
Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H, et al. Functional selectivity and classical concepts of quantitative pharmacology. J Pharmacol Exp Ther. 2007;320:1–13.
pubmed: 16803859
doi: 10.1124/jpet.106.104463
Xu Z, Ikuta T, Kawakami K, Kise R, Qian Y, Xia R, et al. Structural basis of sphingosine-1-phosphate receptor 1 activation and biased agonism. Nat Chem Biol. 2022;18:281–8.
pubmed: 34937912
doi: 10.1038/s41589-021-00930-3
Mirendil H, Thomas EA, De Loera C, Okada K, Inomata Y, Chun J. LPA signaling initiates schizophrenia-like brain and behavioral changes in a mouse model of prenatal brain hemorrhage. Transl Psychiatry. 2015;5:e541.
pubmed: 25849980
pmcid: 4462599
doi: 10.1038/tp.2015.33
Inoue A, Ishiguro J, Kitamura H, Arima N, Okutani M, Shuto A, et al. TGFα shedding assay: an accurate and versatile method for detecting GPCR activation. Nat Methods. 2012;9:1021–9.
pubmed: 22983457
doi: 10.1038/nmeth.2172
Shihoya W, Izume T, Inoue A, Yamashita K, Kadji FMN, Hirata K, et al. Crystal structures of human ET
pubmed: 30413709
pmcid: 6226434
doi: 10.1038/s41467-018-07094-0
Su W, Sun J, Shimizu K, Kadota K. TCC-GUI: a Shiny-based application for differential expression analysis of RNA-Seq count data. BMC Res Notes. 2019;12:133.
pubmed: 30867032
pmcid: 6417217
doi: 10.1186/s13104-019-4179-2
Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, et al. Identification of a primary target of thalidomide teratogenicity. Science. 2010;327:1345–50.
pubmed: 20223979
doi: 10.1126/science.1177319
Lopez-Girona A, Mendy D, Ito T, Miller K, Gandhi AK, Kang J, et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia. 2012;26:2326–35.
pubmed: 22552008
pmcid: 3496085
doi: 10.1038/leu.2012.119
Miyake K, Fukuchi H, Kitaura T, Kimura M, Sarai K, Nakahara T. Pharmacokinetics of amitriptyline and its demethylated metabolite in serum and specific brain regions of rats after acute and chronic administration of amitriptyline. J Pharm Sci. 1990;79:288–91.
pubmed: 2352137
doi: 10.1002/jps.2600790403
Glotzbach RK, Preskorn SH. Brain concentrations of tricyclic antidepressants: single-dose kinetics and relationship to plasma concentrations in chronically dosed rats. Psychopharmacology (Berl). 1982;78:25–7.
pubmed: 6815692
doi: 10.1007/BF00470582
Bolo NR, Hodé Y, Nédélec JF, Lainé E, Wagner G, Macher JP. Brain pharmacokinetics and tissue distribution in vivo of fluvoxamine and fluoxetine by fluorine magnetic resonance spectroscopy. Neuropsychopharmacology. 2000;23:428–38.
pubmed: 10989270
doi: 10.1016/S0893-133X(00)00116-0
Inoue A, Raimondi F, Kadji FMN, Singh G, Kishi T, Uwamizu A, et al. Illuminating G-Protein-Coupling Selectivity of GPCRs. Cell. 2019;177:1933–47.e25.
pubmed: 31160049
pmcid: 6773469
doi: 10.1016/j.cell.2019.04.044
Ehlert FJ, Griffin MT, Sawyer GW, Bailon R. A simple method for estimation of agonist activity at receptor subtypes: comparison of native and cloned M3 muscarinic receptors in guinea pig ileum and transfected cells. J Pharmacol Exp Ther. 1999;289:981–92.
pubmed: 10215678
Petit-Demouliere B, Chenu F, Bourin M. Forced swimming test in mice: a review of antidepressant activity. Psychopharmacology. 2005;177:245–55.
pubmed: 15609067
doi: 10.1007/s00213-004-2048-7
Mezadri TJ, Batista GM, Portes AC, Marino-Neto J, Lino-de-Oliveira C. Repeated rat-forced swim test: reducing the number of animals to evaluate gradual effects of antidepressants. J Neurosci Methods. 2011;195:200–5.
pubmed: 21167866
doi: 10.1016/j.jneumeth.2010.12.015
Yi LT, Li J, Liu Q, Geng D, Zhou YF, Ke XQ, et al. Antidepressant-like effect of oleanolic acid in mice exposed to the repeated forced swimming test. J Psychopharmacol. 2013;27:459–68.
pubmed: 23151611
doi: 10.1177/0269881112467090
Contos JJ, Fukushima N, Weiner JA, Kaushal D, Chun J. Requirement for the lpA1 lysophosphatidic acid receptor gene in normal suckling behavior. Proc Natl Acad Sci USA. 2000;97:13384–9.
pubmed: 11087877
pmcid: 27233
doi: 10.1073/pnas.97.24.13384
Kajitani N, Okada-Tsuchioka M, Kano K, Omori W, Boku S, Aoki J, et al. Differential anatomical and cellular expression of lysophosphatidic acid receptor 1 in adult mouse brain. Biochem Biophys Res Commun. 2020;531:89–95.
pubmed: 32718668
doi: 10.1016/j.bbrc.2020.05.068
Bacq A, Balasse L, Biala G, Guiard B, Gardier AM, Schinkel A, et al. Organic cation transporter 2 controls brain norepinephrine and serotonin clearance and antidepressant response. Mol Psychiatry. 2012;17:926–39.
pubmed: 21769100
doi: 10.1038/mp.2011.87
Murph MM, Scaccia LA, Volpicelli LA, Radhakrishna H. Agonist-induced endocytosis of lysophosphatidic acid-coupled LPA1/EDG-2 receptors via a dynamin2- and Rab5-dependent pathway. J Cell Sci. 2003;116:1969–80.
pubmed: 12668728
doi: 10.1242/jcs.00397
Cahill KM, Huo Z, Tseng GC, Logan RW, Seney ML. Improved identification of concordant and discordant gene expression signatures using an updated rank-rank hypergeometric overlap approach. Sci Rep. 2018;8:9588.
pubmed: 29942049
pmcid: 6018631
doi: 10.1038/s41598-018-27903-2
Plaisier SB, Taschereau R, Wong JA, Graeber TG. Rank-rank hypergeometric overlap: identification of statistically significant overlap between gene-expression signatures. Nucleic Acids Res. 2010;38:e169.
pubmed: 20660011
pmcid: 2943622
doi: 10.1093/nar/gkq636
Krämer A, Green J, Pollard J, Tugendreich S. Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics. 2014;30:523–30.
pubmed: 24336805
doi: 10.1093/bioinformatics/btt703
Yung YC, Stoddard NC, Chun J. LPA receptor signaling: pharmacology, physiology, and pathophysiology. J Lipid Res. 2014;55:1192–214.
pubmed: 24643338
pmcid: 4076099
doi: 10.1194/jlr.R046458
Yu FX, Zhao B, Panupinthu N, Jewell JL, Lian I, Wang LH, et al. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell. 2012;150:780–91.
pubmed: 22863277
pmcid: 3433174
doi: 10.1016/j.cell.2012.06.037
Bagot RC, Cates HM, Purushothaman I, Vialou V, Heller EA, Yieh L, et al. Ketamine and Imipramine reverse transcriptional signatures of susceptibility and induce resilience-specific gene expression profiles. Biol Psychiatry. 2017;81:285–95.
pubmed: 27569543
doi: 10.1016/j.biopsych.2016.06.012
Salvadore G, Quiroz JA, Machado-Vieira R, Henter ID, Manji HK, Zarate CA. The neurobiology of the switch process in bipolar disorder: a review. J Clin Psychiatry. 2010;71:1488–501.
pubmed: 20492846
pmcid: 3000635
doi: 10.4088/JCP.09r05259gre
Holick KA, Lee DC, Hen R, Dulawa SC. Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor. Neuropsychopharmacology. 2008;33:406–17.
pubmed: 17429410
doi: 10.1038/sj.npp.1301399
Karpova NN, Lindholm J, Pruunsild P, Timmusk T, Castrén E. Long-lasting behavioural and molecular alterations induced by early postnatal fluoxetine exposure are restored by chronic fluoxetine treatment in adult mice. Eur Neuropsychopharmacol. 2009;19:97–108.
pubmed: 18973993
doi: 10.1016/j.euroneuro.2008.09.002
Razzoli M, Carboni L, Andreoli M, Michielin F, Ballottari A, Arban R. Strain-specific outcomes of repeated social defeat and chronic fluoxetine treatment in the mouse. Pharmacol Biochem Behav. 2011;97:566–76.
pubmed: 20863846
doi: 10.1016/j.pbb.2010.09.010
Ihne JL, Fitzgerald PJ, Hefner KR, Holmes A. Pharmacological modulation of stress-induced behavioral changes in the light/dark exploration test in male C57BL/6 J mice. Neuropharmacology. 2012;62:464–73.
pubmed: 21906605
doi: 10.1016/j.neuropharm.2011.08.045
Caldarone BJ, Karthigeyan K, Harrist A, Hunsberger JG, Wittmack E, King SL, et al. Sex differences in response to oral amitriptyline in three animal models of depression in C57BL/6 J mice. Psychopharmacology (Berl). 2003;170:94–101.
pubmed: 12879206
doi: 10.1007/s00213-003-1518-7
Caldarone BJ, Harrist A, Cleary MA, Beech RD, King SL, Picciotto MR. High-affinity nicotinic acetylcholine receptors are required for antidepressant effects of amitriptyline on behavior and hippocampal cell proliferation. Biol Psychiatry. 2004;56:657–64.
pubmed: 15522249
doi: 10.1016/j.biopsych.2004.08.010
Wróbel A, Serefko A, Wlaź P, Poleszak E. The depressogenic-like effect of acute and chronic treatment with dexamethasone and its influence on the activity of antidepressant drugs in the forced swim test in adult mice. Prog Neuropsychopharmacol Biol Psychiatry. 2014;54:243–8.
pubmed: 24984273
doi: 10.1016/j.pnpbp.2014.06.008
Gupta G, Jia Jia T, Yee Woon L, Kumar Chellappan D, Candasamy M, Dua K. Pharmacological evaluation of antidepressant-like effect of Genistein and its combination with Amitriptyline: An acute and chronic study. Adv Pharmacol Sci. 2015;2015:164943.
pubmed: 26681936
pmcid: 4670631
Kim HJ, Park SD, Lee RM, Lee BH, Choi SH, Hwang SH, et al. Gintonin attenuates depressive-like behaviors associated with alcohol withdrawal in mice. J Affect Disord. 2017;215:23–9.
pubmed: 28314177
doi: 10.1016/j.jad.2017.03.026
Tsuchioka M, Takebayashi M, Hisaoka K, Maeda N, Nakata Y. Serotonin (5-HT) induces glial cell line-derived neurotrophic factor (GDNF) mRNA expression via the transactivation of fibroblast growth factor receptor 2 (FGFR2) in rat C6 glioma cells. J Neurochem. 2008;106:244–57.
pubmed: 18363829
doi: 10.1111/j.1471-4159.2008.05357.x
Regenthal R, Krueger M, Koeppel C, Preiss R. Drug levels: therapeutic and toxic serum/plasma concentrations of common drugs. J Clin Monit Comput. 1999;15:529–44.
pubmed: 12578052
doi: 10.1023/A:1009935116877
Fisar Z, Krulik R, Fuksová K, Sikora J. Imipramine distribution among red blood cells, plasma and brain tissue. Gen Physiol Biophys. 1996;15:51–64.
pubmed: 8902557
Hrdina PD, Dubas TC. Brain distribution and kinetics of desipramine in the rat. Can J Physiol Pharmacol. 1981;59:163–7.
pubmed: 7225943
doi: 10.1139/y81-027
Casarotto PC, Girych M, Fred SM, Kovaleva V, Moliner R, Enkavi G, et al. Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. Cell. 2021;184:1299–313.e19.
pubmed: 33606976
pmcid: 7938888
doi: 10.1016/j.cell.2021.01.034
Castilla-Ortega E, Pavón FJ, Sánchez-Marín L, Estivill-Torrús G, Pedraza C, Blanco E, et al. Both genetic deletion and pharmacological blockade of lysophosphatidic acid LPA1 receptor results in increased alcohol consumption. Neuropharmacology. 2016;103:92–103.
pubmed: 26700247
doi: 10.1016/j.neuropharm.2015.12.010
Moreno-Fernández RD, Nieto-Quero A, Gómez-Salas FJ, Chun J, Estivill-Torrús G, Rodríguez de Fonseca F, et al. Effects of genetic deletion versus pharmacological blockade of the LPA
doi: 10.1242/dmm.035519
Ohta H, Sato K, Murata N, Damirin A, Malchinkhuu E, Kon J, et al. Ki16425, a subtype-selective antagonist for EDG-family lysophosphatidic acid receptors. Mol Pharmacol. 2003;64:994–1005.
pubmed: 14500756
doi: 10.1124/mol.64.4.994
Choi JW, Herr DR, Noguchi K, Yung YC, Lee CW, Mutoh T, et al. LPA receptors: subtypes and biological actions. Annu Rev Pharmacol Toxicol. 2010;50:157–86.
pubmed: 20055701
doi: 10.1146/annurev.pharmtox.010909.105753
Moreno-Fernández RD, Rosell-Valle C, Bacq A, Zanoletti O, Cifuentes M, Pérez-Martín M, et al. LPA
pubmed: 31811875
doi: 10.1016/j.neuropharm.2019.107896
Rosell-Valle C, Pedraza C, Manuel I, Moreno-Rodríguez M, Rodríguez-Puertas R, Castilla-Ortega E, et al. Chronic central modulation of LPA/LPA receptors-signaling pathway in the mouse brain regulates cognition, emotion, and hippocampal neurogenesis. Prog Neuropsychopharmacol Biol Psychiatry. 2021;108:110156.
pubmed: 33152386
doi: 10.1016/j.pnpbp.2020.110156
Shukla AK, Singh G, Ghosh E. Emerging structural insights into biased GPCR signaling. Trends Biochem Sci. 2014;39:594–602.
pubmed: 25458114
doi: 10.1016/j.tibs.2014.10.001
Latorraca NR, Venkatakrishnan AJ, Dror RO. GPCR dynamics: Structures in motion. Chem Rev. 2017;117:139–55.
pubmed: 27622975
doi: 10.1021/acs.chemrev.6b00177
Cong X, Maurel D, Déméné H, Vasiliauskaité-Brooks I, Hagelberger J, Peysson F, et al. Molecular insights into the biased signaling mechanism of the μ-opioid receptor. Mol Cell. 2021;81:4165–75.e6.
pubmed: 34433090
pmcid: 8541911
doi: 10.1016/j.molcel.2021.07.033
Liu S, Paknejad N, Zhu L, Kihara Y, Ray M, Chun J, et al. Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate. Nat Commun. 2022;13:731.
pubmed: 35136060
pmcid: 8826421
doi: 10.1038/s41467-022-28417-2
Akasaka H, Tanaka T, Sano FK, Matsuzaki Y, Shihoya W, Nureki O. Structure of the active G
pubmed: 36109516
pmcid: 9477835
doi: 10.1038/s41467-022-33121-2
García-Rojo G, Fresno C, Vilches N, Díaz-Véliz G, Mora S, Aguayo F, et al. The ROCK inhibitor fasudil prevents chronic restraint stress-induced depressive-like behaviors and dendritic spine loss in Rat Hippocampus. Int J Neuropsychopharmacol. 2017;20:336–45.
pubmed: 27927737
Fox ME, Chandra R, Menken MS, Larkin EJ, Nam H, Engeln M, et al. Dendritic remodeling of D1 neurons by RhoA/Rho-kinase mediates depression-like behavior. Mol Psychiatry. 2020;25:1022–34.
pubmed: 30120419
doi: 10.1038/s41380-018-0211-5
Sorensen SD, Nicole O, Peavy RD, Montoya LM, Lee CJ, Murphy TJ, et al. Common signaling pathways link activation of murine PAR-1, LPA, and S1P receptors to proliferation of astrocytes. Mol Pharmacol. 2003;64:1199–209.
pubmed: 14573770
doi: 10.1124/mol.64.5.1199
Sramek JJ, Murphy MF, Cutler NR. Sex differences in the psychopharmacological treatment of depression. Dialogues Clin Neurosci. 2016;18:447–57.
pubmed: 28179816
pmcid: 5286730
doi: 10.31887/DCNS.2016.18.4/ncutler