Adreno-melatonin receptor complexes control ion homeostasis and intraocular pressure - their disruption contributes to hypertensive glaucoma

Often, glaucoma presents with elevated eye hydrostatic pressure, which is regulated by endogenous melatonin. Phenylephrine increases cytoplasmic [Ca2+ ], via α1 -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. Gs /Gi /Gq 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

Often, glaucoma presents with elevated eye hydrostatic pressure, which is regulated by endogenous melatonin. Phenylephrine increases cytoplasmic [Ca2+ ], via α1 -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. Gs /Gi /Gq 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

α1 -adreno- and melatonin receptors form functional complexes in which the C-terminal tail of the adrenoceptor plays a role. Remarkably, activation of α1 -adrenoceptors in these complexes did not lead to cytosolic Ca2+ increases, suggesting Gs instead of Gq 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 α1 -adrenoceptors could normalize pressure in glaucoma. Remarkably, co-instillation of melatonin and prazosin, an α1 -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.