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Abstract #84866 Published in IGR 21-1
Adreno-melatonin receptor complexes control ion homeostasis and intraocular pressure - their disruption contributes to hypertensive glaucoma
Alkozi HA; Navarro G; Aguinaga D; Reyes-Resina I; Reyes-Resina I; Sanchez-Naves J; Pérez de Lara MJ; Franco R; Pintor JBritish Journal of Pharmacology 2020; 0:
BACKGROUND AND PURPOSE: Often, glaucoma presents with elevated eye hydrostatic pressure, which is regulated by endogenous melatonin. Phenylephrine increases cytoplasmic [Ca ], via α -adrenoceptor activation, that is detrimental in glaucoma. The aims of this study were (a) to elucidate the role of melatonin receptors in humour production and intraocular pressure (IOP) maintenance and (b) to identify glaucoma-relevant melatonin-adrenoceptor interactions. EXPERIMENTAL APPROACH: Biophysical and proximity ligation assays were performed to identify interactions in heterologous expression systems, in cell lines and in human eyes. G /G /G signalling was investigated in these systems and in cells producing aqueous humour. IOP was determined in a mice model of glaucoma. Retinography and topically pharmacological treatment were performed in control and in glaucomatous mice. KEY RESULTS: α -adreno- and melatonin receptors form functional complexes in which the C-terminal tail of the adrenoceptor plays a role. Remarkably, activation of α -adrenoceptors in these complexes did not lead to cytosolic Ca increases, suggesting G instead of G coupling is involved. The number of these complexes significantly decreased in models of glaucoma and, importantly, in human samples from glaucoma patients. This has led to hypothesize that melatonin, a hypotensive agent, plus blockade of α -adrenoceptors could normalize pressure in glaucoma. Remarkably, co-instillation of melatonin and prazosin, an α -adrenoceptor antagonist, resulted in long-term decreases in IOP in a well-established animal model of glaucoma. CONCLUSIONS AND IMPLICATIONS: The findings are instrumental to understand the physiological function of melatonin in the eye and its potential to address eye pathologies by targeting melatonin receptors and their complexes.
Department of Biochemistry and Molecular Biology, Faculty of Optics and Optometry, University Complutense of Madrid, Madrid, Spain.
Full articleClassification:
6.1.3 Factors affecting IOP (Part of: 6 Clinical examination methods > 6.1 Intraocular pressure measurement; factors affecting IOP)
3.8 Pharmacology (Part of: 3 Laboratory methods)
3.6 Cellular biology (Part of: 3 Laboratory methods)
