Cellular and molecular effects of unoprostone as a BK channel activator

Effects of unoprostone isopropyl (unoprostone), a prostaglandin metabolite analog; latanoprost, a PGF_2α analog; and PGF_2α were examined in HCN-1A cells, a model system for studies of large conductance Ca²⁺ activated K⁺(BK) channel activator-based neuroprotective agents. Unoprostone and latanoprost, both used as anti-glaucoma agents, have been suggested to act through FP receptors and have neuroprotective effects. Ion channel activation, plasma membrane polarization, [Ca²⁺]_i changes and protection against long-term irreversible glutamate-induced [Ca²⁺]_i increases were studied. Unoprostone activated iberiotoxin (IbTX)-sensitive BK channels in HCN-1A cells with an EC₅₀ of 0.6 ± 0.2 nM and had no effect on Cl⁻ currents. Unoprostone caused IbTX-sensitive plasma membrane hyperpolarization that was insensitive to AL8810, an FP receptor antagonist. In contrast, latanoprost and PGF_2α activated a Cl⁻ current sensitive to [Ca²⁺]_i chelation, tamoxifen and AL8810, and caused IbTX-insensitive, AL8810-sensitive membrane depolarization consistent with FP receptor-mediated Ca²⁺ signaling Cl⁻ current activation. Latanoprost and PGF_2α, but not unoprostone, increased [Ca²⁺]_i. Unoprostone, PGF_2α only partially, but not latanoprost protected HCN-1A cells against glutamate-induced Ca²⁺ deregulation. These findings show that unoprostone has a distinctly different mechanism of action from latanoprost and PGF_2α. Whether unoprostone affects the BK channel directly or an unidentified signaling mechanism has not been determined.