Expression of Melatonin and Dopamine D₃ Receptor Heteromers in Eye Ciliary Body Epithelial Cells and Negative Correlation with Ocular Hypertension.

BACKGROUND:Experiments in the late nineties showed an inverse relationship in the eye levels of melatonin and dopamine, thereby constituting an example of eye parameters that are prone to circadian variations. The underlying mechanisms are not known but these relevant molecules act via specific cell surface dopamine and melatonin receptors. This study investigated whether these receptors formed heteromers whose function impact on eye physiology. We performed biophysical assays to identify interactions in heterologous systems. Particular heteromer functionality was detected using Gi coupling, MAPK activation, and label-free assays. The expression of the heteroreceptor complexes was assessed using proximity ligation assays in cells producing the aqueous humor and human eye samples. Dopamine D₃ receptors (D₃Rs) were identified in eye ciliary body epithelial cells. We discovered heteromers formed by D₃R and either MT₁ (MT₁R) or MT₂ (MT₂R) melatonin receptors. Heteromerization led to the blockade of D₃R-Gi coupling and regulation of signaling to the MAPK pathway. Heteromer expression was negatively correlated with intraocular hypertension. CONCLUSIONS:Heteromers likely mediate melatonin and dopamine actions in structures regulating intraocular pressure. Significant expression of D₃R-MT₁R and D₃R-MT₁R was associated with normotensive conditions, whereas expression diminished in a cell model of hypertension. A clear trend of expression reduction was observed in samples from glaucoma cases. The trend was marked but no statistical analysis was possible as the number of available eyes was 2.

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