PT  - JOURNAL ARTICLE
AU  - Hanan Awad Alkozi
AU  - Gemma Navarro
AU  - David Aguinaga
AU  - Irene Reyes-Resina
AU  - Juan Sanchez-Naves
AU  - Maria J Perez de Lara
AU  - Rafael Franco
AU  - Jesus Pintor
TI  - Adrenergic-melatonin heteroreceptor complexes are key in controlling ion homeostasis and intraocular eye pressure and their disruption contributes to hypertensive glaucoma
AID  - 10.1101/636688
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 636688
4099  - http://biorxiv.org/content/early/2019/05/14/636688.short
4100  - http://biorxiv.org/content/early/2019/05/14/636688.full
AB  - Melatonin regulates intraocular pressure (IOP) whose increase leads to glaucoma and eye nerve degeneration. Aiming at elucidating the role of melatonin receptors in humour production and IOP maintenance, we here demonstrate that glaucoma correlates with disassembly of α1-adrenergic/melatonin receptor functional units in cells producing the aqueous humour. Remarkably, α1-adrenoceptor-containing complexes do not coupled to the cognate Gq protein and, hence, phenylephrine activation of these receptors does not lead to Ca2+ mobilization. Functional complexes are significantly decreased in models of glaucoma and, more importantly, in human samples of glaucoma patients (GP). In such glaucomatous conditions phenylephrine produces, via α1-adrenoceptor activation, an increase in cytoplasmic [Ca2+] that is detrimental in glaucoma. The results led to hypothesize that using melatonin, a hypotensive agent, plus blockade of α1-adrenergic receptors may normalize pressure in glaucoma. Remarkably, co-instillation of melatonin and prazosin, a α1-adrenergic receptor antagonist, results in long-term decreases in IOP in a well-established animal model of glaucoma. 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.