The goal of this project is to understand the roles of the a2-adrenergic and prostaglandin EP receptor subtypes in the pharmacology and physiology of aqueous secretion by the mammalian ocular ciliary epithelium. Towards this end the PI will continue the work that he has started to identify the cellular and subcellular localization of the a2-adrenergic receptor subtypes in the ciliary epithelium using immunofluorescence microscopy. He will also develop antibodies to the prostaglandin EP receptor subtypes and use these in conjunction with the polymerase chain reaction for the localization of prostaglandin receptors in the ciliary epithelium. Of particular interest is the possible interaction of the a2-adrenergic and prostaglandin receptors with the functional activity of proteins that are involved with secretion, such as the Na+/K+/2C1- co-transporter and the aquaporins or water channels. In this regard, the PI has very exciting preliminary data which shows that forskolin, a modulator of intracellular cAMP, can stimulate the water permeability of aquaporin-1 and can activate a novel cationic conductance by the water channel. This suggests that receptors which can modulate intracellular cAMP formation, such as the a2-adrenergic and prostaglandin EP, can potentially regulate the activity of aquaporin-1. In fact, following heterologous expression of aquaporin-1 and prostaglandin EP2 receptors in Xenopus oocytes we can show PGE2-activation of a cationic conductance by aquaporin-1. These studies will contribute to our understanding of the regulation of aqueous secretion in the ciliary epithelium and could be potentially very important towards our understanding of the pathophysiology and treatment of glaucoma.
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