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Cellular and molecular effects of unoprostone as a BK channel activator.
Cuppoletti, John; Malinowska, Danuta H; Tewari, Kirti P; Chakrabarti, Jayati; Ueno, Ryuji.
Affiliation
  • Cuppoletti 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
Biochim Biophys Acta ; 1768(5): 1083-92, 2007 May.
Article in En | MEDLINE | ID: mdl-17307133
ABSTRACT
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.
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Collection: 01-internacional Database: MEDLINE Main subject: Dinoprost / Ion Channel Gating / Potassium Channels, Calcium-Activated Type of study: Prognostic_studies Limits: Humans Language: En Journal: Biochim Biophys Acta Year: 2007 Type: Article Affiliation country: United States
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Collection: 01-internacional Database: MEDLINE Main subject: Dinoprost / Ion Channel Gating / Potassium Channels, Calcium-Activated Type of study: Prognostic_studies Limits: Humans Language: En Journal: Biochim Biophys Acta Year: 2007 Type: Article Affiliation country: United States