Adrenergic‐melatonin receptor complexes control ion homeostasis and intraocular pressure and their disruption contributes to hypertensive glaucoma

Background and Purpose: Often, glaucoma courses with elevated eye hydrostatic pression, which is regulated by endogenous melatonin. Via α1‐adrenoceptor activation, phenylephrine increases cytoplasmic [Ca2+] that is detrimental in glaucoma. The aims of the paper were i) elucidating the role of melatonin receptors in humour production and intraocular pressure (IOP) maintenance and ii) identifying glaucoma relevant melatonin‐adrenergic interactions. Experimental approach: Biophysical and proximity ligation assays were performed to identify interactions in heterologous systems, in cell lines and in human eyes. Gs/Gi/Gq signaling was investigated in heterologous systems and cells producing the 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: α1‐adrenergic and melatonin receptors form functional complexes in which the C‐terminal tail of the adrenergic receptor play a relevant role. Remarkably, activation of α1‐adrenoceptors in the complex did not lead to cytosolic Ca2+ increases, suggesting Gs instead of Gq coupling. The number of complexes significantly decreased in models of glaucoma and, more importantly, in human samples of glaucoma patients. The results led to hypothesize that melatonin, a hypotensive agent, plus blockade of α1‐adrenergic receptors could normalize pressure in glaucoma. Remarkably, co‐instillation of melatonin and prazosin, an α1‐adrenergic receptor antagonist, resulted in long‐term decreases in IOP in a well‐established animal model of glaucoma. Conclusions & 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