Newer targets for modulation of intraocular pressure: focus on adenosine receptor signaling pathways

The homeostatic role of adenosine in regulating intraocular pressure (IOP) is now widely recognized, and hence, the drugs targeting adenosine receptors have become the focus of investigation. In this review, we summarize the adenosine receptor signaling pathways, which could be potential therapeutic targets for the management of glaucoma.

This review presents a brief summary of the current hypotheses explaining the increased resistance in the trabecular meshwork outflow pathways and the role of adenosine in regulating the outflow pathway resistance. The intraocular distribution of adenosine receptor subtypes and their structure is described. The adenosine receptor signaling pathways, including activation of adenylyl cyclase, phospholipase-inositol triphosphate-diacylglycerol and phosphatidylinositol-3-kinase and their link to MAPK pathways leading to changes in gene transcription are discussed in detail. The literature search for this review was done using PubMed using several key words such as adenosine, receptors, signaling pathways, trabecular meshwork, ciliary body, IOP, G proteins, GPCR, adenylyl cyclase, phospholipase C, ERK1/2 and MAPKs.

Besides adenosine receptor agonists and antagonists, drugs targeting intracellular signaling molecules, such as Ras proteins, small GTPase (Rho), Epac-specific cAMP analogs and Rap and Raf-targeted therapies may be useful strategies in regulating IOP.