{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T19:53:19Z","timestamp":1778701999991,"version":"3.51.4"},"reference-count":34,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T00:00:00Z","timestamp":1608163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000957","name":"Alzheimer's Association","doi-asserted-by":"publisher","award":["AARG-NTF-18-565227"],"award-info":[{"award-number":["AARG-NTF-18-565227"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mitochondria in neurons contribute to energy supply, the regulation of synaptic transmission, Ca2+ homeostasis, neuronal excitability, and stress adaptation. In recent years, several studies have highlighted that the neurotransmitter serotonin (5-HT) plays an important role in mitochondrial biogenesis in cortical neurons, and regulates mitochondrial activity and cellular function in cardiomyocytes. 5-HT exerts its diverse actions by binding to cell surface receptors that are classified into seven distinct families (5-HT1 to 5-HT7). Recently, it was shown that 5-HT3 and 5-HT4 receptors are located on the mitochondrial membrane and participate in the regulation of mitochondrial function. Furthermore, it was observed that activation of brain 5-HT7 receptors rescued mitochondrial dysfunction in female mice from two models of Rett syndrome, a rare neurodevelopmental disorder characterized by severe behavioral and physiological symptoms. Our Western blot analyses performed on cell-lysate and purified mitochondria isolated from neuronal cell line SH-SY5Y showed that 5-HT7 receptors are also expressed into mitochondria. Maximal binding capacity (Bmax) obtained by Scatchard analysis on purified mitochondrial membranes was 0.081 pmol\/mg of 5-HT7 receptor protein. Lastly, we evaluated the effect of selective 5-HT7 receptor agonist LP-211 and antagonist (inverse agonist) SB-269970 on mitochondrial respiratory chain (MRC) cytochrome c oxidase activity on mitochondria from SH-SY5Y cells. Our findings provide the first evidence that 5-HT7 receptor is also expressed in mitochondria.<\/jats:p>","DOI":"10.3390\/ijms21249629","type":"journal-article","created":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T10:42:47Z","timestamp":1608201767000},"page":"9629","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Mitochondrial Membranes of Human SH-SY5Y Neuroblastoma Cells Express Serotonin 5-HT7 Receptor"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1883-0227","authenticated-orcid":false,"given":"Alessandra","family":"Tempio","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze Biomediche e Biotecnologiche, Universit\u00e0 degli Studi di Catania, via S. Sofia 97, 95123 Catania, Italy"},{"name":"Biofordrug srl, via Dante 99, 70019 Triggiano (Bari), Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2846-1744","authenticated-orcid":false,"given":"Mauro","family":"Niso","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia-Scienze del Farmaco, Universit\u00e0 degli Studi di Bari Aldo Moro, via Orabona 4, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5266-1156","authenticated-orcid":false,"given":"Luna","family":"Laera","sequence":"additional","affiliation":[{"name":"Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica, Universit\u00e0 degli Studi di Bari Aldo Moro, via Orabona 4, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucia","family":"Trisolini","sequence":"additional","affiliation":[{"name":"Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica, Universit\u00e0 degli Studi di Bari Aldo Moro, via Orabona 4, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6039-9365","authenticated-orcid":false,"given":"Maria","family":"Favia","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia-Scienze del Farmaco, Universit\u00e0 degli Studi di Bari Aldo Moro, via Orabona 4, 70125 Bari, Italy"},{"name":"Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica, Universit\u00e0 degli Studi di Bari Aldo Moro, via Orabona 4, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucia","family":"Ciranna","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche e Biotecnologiche, Universit\u00e0 degli Studi di Catania, via S. Sofia 97, 95123 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Domenico","family":"Marzulli","sequence":"additional","affiliation":[{"name":"Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), National Research Council (CNR), 70126 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8035-8368","authenticated-orcid":false,"given":"Giuseppe","family":"Petrosillo","sequence":"additional","affiliation":[{"name":"Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), National Research Council (CNR), 70126 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1816-548X","authenticated-orcid":false,"given":"Ciro Leonardo","family":"Pierri","sequence":"additional","affiliation":[{"name":"Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica, Universit\u00e0 degli Studi di Bari Aldo Moro, via Orabona 4, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2443-1174","authenticated-orcid":false,"given":"Enza","family":"Lacivita","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia-Scienze del Farmaco, Universit\u00e0 degli Studi di Bari Aldo Moro, via Orabona 4, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcello","family":"Leopoldo","sequence":"additional","affiliation":[{"name":"Biofordrug srl, via Dante 99, 70019 Triggiano (Bari), Italy"},{"name":"Dipartimento di Farmacia-Scienze del Farmaco, Universit\u00e0 degli Studi di Bari Aldo Moro, via Orabona 4, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1124\/mol.117.111062","article-title":"G Protein-Coupled receptors as targets for approved drugs: How many targets and how many Drugs?","volume":"93","author":"Sriram","year":"2018","journal-title":"Mol. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1021\/acschemneuro.7b00516","article-title":"Intracellular GPCRs play key roles in synaptic plasticity","volume":"9","author":"Jong","year":"2018","journal-title":"ACS Chem. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1002\/jcb.20144","article-title":"Mitochondrial P2Y-Like receptors link cytosolic adenosine nucleotides to mitochondrial calcium uptake","volume":"92","author":"Belous","year":"2004","journal-title":"J. Cell. Biochem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.peptides.2012.09.016","article-title":"Subcellular characteristics of functional intracellular renin-angiotensin systems","volume":"38","author":"Abadir","year":"2012","journal-title":"Peptides"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"37336","DOI":"10.1038\/srep37336","article-title":"5HTR3 and 5-HTR4 located on the mitochondrial membrane and functionally regulated mitochondrial functions","volume":"6","author":"Wang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"E7997","DOI":"10.1073\/pnas.1705768114","article-title":"Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release","volume":"114","author":"Suofu","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"8475","DOI":"10.1021\/acs.jmedchem.7b01898","article-title":"Structure-activity relationships and therapeutic potentials of 5-HT7 receptor ligands: An update","volume":"61","author":"Modica","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Crispino, M., Volpicelli, F., and Perrone-Capano, C. (2020). Role of the serotonin receptor 7 in brain plasticity: From development to disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21020505"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"353","DOI":"10.3389\/fnmol.2018.00353","article-title":"Activation of Serotonin 5-HT7 Receptors Modulates Hippocampal Synaptic Plasticity by Stimulation of Adenylate Cyclases and Rescues Learning and Behavior in a Mouse Model of Fragile X Syndrome","volume":"11","author":"Costa","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.neulet.2010.06.036","article-title":"LP-211 is a brain penetrant selective agonist for the serotonin 5-HT7 receptor","volume":"481","author":"Hedlund","year":"2010","journal-title":"Neurosci. Lett."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.neuropharm.2017.04.024","article-title":"Stimulation of the brain serotonin receptor 7 rescues mitochondrial dysfunction in female mice from two models of Rett syndrome","volume":"121","author":"Valenti","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.neuropharm.2018.10.018","article-title":"Rescue of prepulse inhibition deficit and brain mitochondrial dysfunction by pharmacological stimulation of the central serotonin receptor 7 in a mouse model of CDKL5 Deficiency Disorder","volume":"144","author":"Vigli","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8200","DOI":"10.1523\/JNEUROSCI.1157-19.2019","article-title":"Pleiotropic mitochondria: The influence of mitochondria on neuronal development and disease","volume":"39","author":"Rangaraju","year":"2019","journal-title":"J. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s10048-012-0350-9","article-title":"Comprehensive cytogenomic profile of the in vitro neuronal model SH-SY5Y","volume":"14","author":"Yusuf","year":"2013","journal-title":"Neurogenetics"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"391","DOI":"10.3389\/fnbeh.2014.00391","article-title":"5-HT7 receptor activation promotes an increase in TrkB receptor expression and phosphorylation","volume":"8","author":"Samarajeewa","year":"2014","journal-title":"Front. Behav. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.neulet.2012.01.016","article-title":"Activation of 5-HT7 receptors increases neuronal platelet-derived growth factor \u03b2 receptor expression","volume":"511","author":"Vasefi","year":"2012","journal-title":"Neurosci. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.ntt.2019.01.002","article-title":"Protective effect of 5-HT7 receptor activation against glutamate-induced neurotoxicity in human neuroblastoma SH-SY5Y cells via antioxidative and antiapoptotic pathways","volume":"72","author":"Yuksel","year":"2019","journal-title":"Neurotoxicol. Teratol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"112395","DOI":"10.1016\/j.ejmech.2020.112395","article-title":"Privileged scaffold-based design to identify a novel drug-like 5-HT7 receptor-preferring agonist to target Fragile X syndrome","volume":"199","author":"Lacivita","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1046\/j.1471-4159.1997.68041372.x","article-title":"Four 5-hydroxytryptamine7 (5-HT7) receptor isoforms in human and rat produced by alternative splicing: Species differences due to altered intron-exon organization","volume":"68","author":"Heidmann","year":"1997","journal-title":"J. Neurochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/0896-6273(93)90149-L","article-title":"A novel adenylyl cyclase-activating serotonin receptor (5-HT7) implicated in the regulation of mammalian circadian rhythms","volume":"11","author":"Lovenberg","year":"1993","journal-title":"Neuron"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1042\/BST20120235","article-title":"Palmitoylation of serotonin receptors","volume":"41","author":"Gorinski","year":"2013","journal-title":"Biochem. Soc. Trans."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/sj.bjp.0705936","article-title":"Functional expression of the serotonin 5-HT7 receptor in human glioblastoma cell lines","volume":"143","author":"Bernhard","year":"2004","journal-title":"Br. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"11028","DOI":"10.1073\/pnas.1821332116","article-title":"Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1-PGC-1\u03b1 axis","volume":"116","author":"Fanibunda","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1021\/jm991151j","article-title":"A novel, potent, and selective 5-HT7 antagonist: (R)-3-(2-(2-(4-methylpiperidin-1-yl)ethyl)pyrrolidine-1-sulfonyl) phen ol (SB-269970)","volume":"43","author":"Lovell","year":"2000","journal-title":"J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/sj.bjp.0703318","article-title":"[3H]-SB-269970--A selective antagonist radioligand for 5-HT7 receptors","volume":"130","author":"Thomas","year":"2000","journal-title":"Br. J. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3884","DOI":"10.1523\/JNEUROSCI.09-11-03884.1989","article-title":"Brain cytochrome oxidase: Purification, antibody production, and immunohistochemical\/histochemical correlations in the CNS","volume":"9","author":"Hevner","year":"1989","journal-title":"J. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/978-1-4614-3573-0_10","article-title":"Phosphorylation of mammalian cytochrome c and cytochrome c oxidase in the regulation of cell destiny: Respiration, apoptosis, and human disease","volume":"748","author":"Lee","year":"2012","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/nature20127","article-title":"A cannabinoid link between mitochondria and memory","volume":"539","author":"Desprez","year":"2016","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1038\/nprot.2012.058","article-title":"Assessment of mitochondrial respiratory chain enzymatic activities on tissues and cultured cells","volume":"7","author":"Spinazzi","year":"2012","journal-title":"Nat. Protoc."},{"key":"ref_30","first-page":"199","article-title":"cAMP and mitochondria","volume":"28","author":"Valsecchi","year":"2013","journal-title":"Physiology (Bethesda)"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"18614","DOI":"10.1074\/jbc.M401135200","article-title":"Mitochondrial dysfunction and oxidative damage in parkin-deficient mice","volume":"279","author":"Palacino","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1007\/s00210-004-0961-2","article-title":"Antiproliferative and cytotoxic effects of some sigma2 agonists and sigma1 antagonists in tumour cell lines","volume":"370","author":"Colabufo","year":"2004","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"318","DOI":"10.3389\/fnbeh.2014.00318","article-title":"The serotonin receptor 7 and the structural plasticity of brain circuits","volume":"8","author":"Volpicelli","year":"2014","journal-title":"Front. Behav. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.cophys.2018.03.009","article-title":"Emerging roles of mitochondria in synaptic transmission and neurodegeneration","volume":"3","author":"Lee","year":"2018","journal-title":"Curr. Opin. Physiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/24\/9629\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:46:34Z","timestamp":1760179594000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/24\/9629"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,17]]},"references-count":34,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["ijms21249629"],"URL":"https:\/\/doi.org\/10.3390\/ijms21249629","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,17]]}}}