In ciliary muscle cells, PGF
2α and other FP agonists have been shown to modulate cell function and stimulate MMP secretion.
11 23 40 Recently, it has been shown that FP receptors in HCM cells are coupled to the activation of ERK1/2.
32 In other systems, PGs have been shown to activate MAP kinase signaling pathways
41 42 43 44 45 46 47 and the activation of these pathways modulates the secretion of MMP.
48 49 50 51 Furthermore, ERK1/2 pathways have been shown to play a role in the regulation of MMP secretion from trabecular meshwork cells.
52 However, the cellular event controlling MMP secretion remains poorly understood. In our initial studies to delineate the signaling events that are associated with PGF
2α-induced MMP-2 secretion, HCM cells were treated with an FP agonist in the absence or presence of protein kinase C and MAP kinase pathway inhibitors. Our results demonstrate that PGF
2α-induced secretion of MMP-2 was inhibited in the presence of PKC inhibitor chelerythrine chloride
(Fig. 2) . We have not seen inhibition in PGF
2α-induced MMP-2 secretion in the presence of Go-6976, a classic PKC isoform inhibitor, suggesting that PKC isoform(s) (other than α, β, and γ) are involved in PGF
2α-induced MMP-2 secretion from HCM cells. Furthermore, activity and secretion of MMP-2 in response to PGF
2α was completely inhibited by the pretreatment of cells with the MEK inhibitor, PD-98059
(Fig. 3) , demonstrating that PKC and ERK1/2 activation are involved in the secretion of MMP-2. In addition, administration of PGF
2α and latanoprost acid to HCM cells produced a rapid increase in the activation and phosphorylation of ERK1/2
(Fig. 4) . The inhibition of PGF
2α-induced ERK1/2 activation by FP receptor antagonists AL-8810, PGF
2α-dimethyl amide, and PGF
2α-dimethyl amine also demonstrate that these stimulatory responses are mediated through the activation of FP receptors
(Fig. 5) . PGF
2α-dimethyl amide, and PGF
2α-dimethyl amine have been shown to act as FP receptor antagonists.
53 54