FIG. 1.

Schematic illustration of generation of lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) and the role of their signaling pathways in the regulation of aqueous humor (AH) outflow and intraocular pressure (IOP). LPA is generated largely extracellularly by autotaxin (ATX) by converting lysophosphatidylcholine (LPC) to LPA generated by different phospholipase A2s (PLA2s). In contrast to LPA, S1P is generated predominantly inside the cell by the conversion of sphingosine to S1P by sphingosine kinase. Sphingosine is generated from ceramide by ceramidase. S1P can be transported to extracellular spaces through the ABC transporters and spinster 2. Both LPA and S1P act extracellularly through specific cell surface G-protein coupled receptors (GPCRs) and activate a wide variety of intracellular signaling pathways, including Rho/Rho kinase, Rac/p21-activated kinase (PAK), Ras/extracellular-receptor kinase (ERK), protein kinase (PKC), phospholipase C (PLC), and phospholipase D (PLD). LPA can be also produced intracellularly, and inside the cell, both LPA and S1P are known to serve as second messengers acting through different targets. The GPCR-stimulated signaling events, in turn, influence different cellular processes such as contraction, migration, fibrogenic activity, permeability, cell adhesion, transdifferentiation, and others. These processes in trabecular meshwork and Schlemm's canal cells, in turn, appear to modulate AH outflow and subsequently, IOP.