title: Regulation of intraocular pressure in mice: structural analysis of dopaminergic and serotonergic systems in response to cabergoline.
abstract: Elevated intraocular pressure (IOP) is the main recognized risk factor of glaucoma. To investigate the contribution of dopaminergic and serotonergic systems in IOP regulation, we used cabergoline, a mixed dopamine and serotonin agonist, in C57BL/6J WT and dopamine D₃ receptor knock-out (D₃R⁻/⁻) mice with normal eye pressure or steroid-induced ocular hypertension. Furthermore, we studied the structural basis of the cabergoline-mediated activation of the dopaminergic and serotonergic systems by molecular modeling. Topical application of cabergoline, significantly decreased, in a dose-dependent manner, the intraocular pressure in WT mice, both in an ocular normotensive group (-9, -5 and -2 mmHg with 5%, 1%, and 0.1%, respectively) and an ocular hypertensive group, with a prolonged effect in this latter group. No change of intraocular pressure was observed after topical application of cabergoline in D₃R⁻/⁻ mice. We modeled and optimized, with molecular dynamics, structures of hD₃, h5HT(1A) and h5HT(2A-C) receptors; thereafter we carried out molecular docking of cabergoline. Docking revealed that binding of cabergoline into D₃ and 5HT(1A) receptors is associated with a better desolvation energy in comparison to 5HT(2A-C) binding. In conclusion, the present study support the hypothesis that dopaminergic system is pivotal to regulate IOP and that D₃R represents an intriguing target in the treatment of glaucoma. Furthermore, the structure-based computational approach adopted in this study is able to build and refine structure models of homologous dopaminergic and serotonergic receptors that may be of interest for structure-based drug discovery of ligands, with dopaminergic selectivity or with multi-pharmacological profile, potentially useful to treat optic neuropathies.
authors: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, School of Medicine, University of Catania, 95125, Catania, Italy.
authors: Chiara Bianca Maria
authors: CB
authors: Platania
authors: Gian Marco
authors: GM
authors: Leggio
authors: Filippo
authors: F
authors: Drago
authors: Salvatore
authors: S
authors: Salomone
authors: Claudio
authors: C
authors: Bucolo
mesh_terms: D000818:Animals; D000077465:Cabergoline; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004873:Ergolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009798:Ocular Hypertension / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D011487:Protein Conformation; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry* / Q000378:metabolism; D044403:Receptor, Serotonin, 5-HT2B / Q000737:chemistry* / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D018491:Dopamine Agonists; D004873:Ergolines; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D050637:Receptors, Dopamine D3; D044282:Receptor, Serotonin, 5-HT1A; D000077465:Cabergoline
keywords: Dopaminergic system; GPCR; Intraocular pressure; Molecular modeling; Optic neuropathy; Serotonergic system