Cellular and molecular effects of unoprostone as a BK channel activator.
Effects of unoprostone isopropyl (unoprostone), a prostaglandin metabolite analog; latanoprost, a PGF(2alpha) analog; and PGF(2alpha) were examined in HCN-1A cells, a model system for studies of large conductance Ca(2+) 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, [Ca(2+)](i) changes and protection against long-term irreversible glutamate-induced [Ca(2+)](i) increases were studied. Unoprostone activated iberiotoxin (IbTX)-sensitive BK channels in HCN-1A cells with an EC(50) 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(2alpha) activated a Cl(-) current sensitive to [Ca(2+)](i) chelation, tamoxifen and AL8810, and caused IbTX-insensitive, AL8810-sensitive membrane depolarization consistent with FP receptor-mediated Ca(2+) signaling Cl(-) current activation. Latanoprost and PGF(2alpha), but not unoprostone, increased [Ca(2+)](i). Unoprostone, PGF(2alpha) only partially, but not latanoprost protected HCN-1A cells against glutamate-induced Ca(2+) deregulation. These findings show that unoprostone has a distinctly different mechanism of action from latanoprost and PGF(2alpha). Whether unoprostone affects the BK channel directly or an unidentified signaling mechanism has not been determined.
Cuppoletti
John
J
Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, PO Box 670576, Cincinnati, OH 45267-0576, USA. John.Cuppoletti@uc.edu
Malinowska
Danuta H
DH
Tewari
Kirti P
KP
Chakrabarti
Jayati
J
Ueno
Ryuji
R
D000959:Antihypertensive Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002138:Calibration; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology; D018118:Chloride Channels / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D000077338:Latanoprost; D008564:Membrane Potentials / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors; D013629:Tamoxifen / Q000494:pharmacology
C518977:AL 8810 ethylamide; D000959:Antihypertensive Agents; D002614:Chelating Agents; D018118:Chloride Channels; D010455:Peptides; D024681:Potassium Channels, Calcium-Activated; D011461:Prostaglandins F, Synthetic; D011982:Receptors, Prostaglandin; C034671:prostaglandin F2alpha receptor; D013629:Tamoxifen; D018698:Glutamic Acid; C072630:isopropyl unoprostone; D000077338:Latanoprost; C064719:iberiotoxin; D015237:Dinoprost; D002118:Calcium