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The underlying mechanisms are not known but these relevant molecules act via specific cell surface dopamine and melatonin receptors. This study investigated whether these receptors formed heteromers whose function impact on eye physiology. We performed biophysical assays to identify interactions in heterologous systems. Particular heteromer functionality was detected using Gi coupling, MAPK activation, and label-free assays. The expression of the heteroreceptor complexes was assessed using proximity ligation assays in cells producing the aqueous humor and human eye samples. Dopamine D3 receptors (D3Rs) were identified in eye ciliary body epithelial cells. We discovered heteromers formed by D3R and either MT1 (MT1R) or MT2 (MT2R) melatonin receptors. Heteromerization led to the blockade of D3R-Gi coupling and regulation of signaling to the MAPK pathway. Heteromer expression was negatively correlated with intraocular hypertension. Conclusions: Heteromers likely mediate melatonin and dopamine actions in structures regulating intraocular pressure. Significant expression of D3R\u2013MT1R and D3R\u2013MT1R was associated with normotensive conditions, whereas expression diminished in a cell model of hypertension. A clear trend of expression reduction was observed in samples from glaucoma cases. The trend was marked but no statistical analysis was possible as the number of available eyes was 2.<\/jats:p>","DOI":"10.3390\/cells9010152","type":"journal-article","created":{"date-parts":[[2020,1,9]],"date-time":"2020-01-09T03:07:11Z","timestamp":1578539231000},"page":"152","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Expression of Melatonin and Dopamine D3 Receptor Heteromers in Eye Ciliary Body Epithelial Cells and Negative Correlation with Ocular Hypertension"],"prefix":"10.3390","volume":"9","author":[{"given":"Irene","family":"Reyes-Resina","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biomedicine, School of Biology, Universitat de Barcelona, 08028 Barcelona, Spain"},{"name":"Neuroplasticity Research Group, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany"},{"name":"Centro de Investigaci\u00f3n en Red, Enfermedades Neurodegenerativas, CiberNed, Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanan","family":"Awad Alkozi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Optics and Optometry, University Complutense of Madrid, 28037 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"del Ser-Badia","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n en Red, Enfermedades Neurodegenerativas, CiberNed, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Department de Bioqu\u00edmica i Biologia Molecular, Institut de Neuroci\u00e8ncies, Universitat Aut\u00f2noma de Barcelona, Cerdanyola del Vall\u00e8s, 08193 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4680-8745","authenticated-orcid":false,"given":"Juan","family":"S\u00e1nchez-Naves","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Balearic Islands Institute of Ophthalmology, 07013 Palma de Mallorca, Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaume","family":"Lillo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biomedicine, School of Biology, Universitat de Barcelona, 08028 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n en Red, Enfermedades Neurodegenerativas, CiberNed, Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmina","family":"Jim\u00e9nez","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n en Red, Enfermedades Neurodegenerativas, CiberNed, Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas","family":"Pintor","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Optics and Optometry, University Complutense of Madrid, 28037 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4654-0873","authenticated-orcid":false,"given":"Gemma","family":"Navarro","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n en Red, Enfermedades Neurodegenerativas, CiberNed, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Universitat de Barcelona, 08027 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2549-4919","authenticated-orcid":false,"given":"Rafael","family":"Franco","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n en Red, Enfermedades Neurodegenerativas, CiberNed, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"School of Chemistry, Universitat de Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S1569-2590(05)10005-6","article-title":"Ciliary Body and Ciliary Epithelium","volume":"10","author":"Delamere","year":"2005","journal-title":"Adv. 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