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Author Notes:

Address correspondence to: Douglas C. Eaton, Emory University School of Medicine, Department of Physiology, Whitehead Biomedical Research Building, 615 Michael Street, Atlanta, GA 30322, Phone: 001-(404) 727-7421, Fax: 001-(404) 727-0329, deaton@emory.edu.

Unoprostone is a product of Sucampo.

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Subjects:

Research Funding:

This work was supported by a grant from Sucampo Pharmaceuticals, LLC, and NIH DK R37DK037963 to DCE.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Biophysics
  • BK channels
  • KCNMA1
  • Unoprostone
  • Rescula (R)
  • Single channels
  • Ca2+-dependence
  • INTRACELLULAR CA2+ MOBILIZATION
  • CYTOSOLIC PHOSPHOLIPASE A(2)
  • TRABECULAR MESHWORK CELLS
  • POTASSIUM CHANNELS
  • GH(3) CELLS
  • PHARMACOLOGICAL SYNERGY
  • INTRAOCULAR-PRESSURE
  • RAT-BRAIN
  • ANALOGS
  • FP

Unoprostone activation of BK (K(ca)1.1) channel splice variants

Tools:

Journal Title:

Biochimica et Biophysica Acta - Biomembranes

Volume:

Volume 1848, Number 11

Publisher:

, Pages 2859-2867

Type of Work:

Article | Post-print: After Peer Review

Abstract:

This investigation was conducted to study the relationship between intracellular Ca2+ and activation of large conductance Ca2+-activated K+ (BK) currents by unoprostone, the first synthetic docosanoid. We used HEK293 cells stably transfected with two BK channel splice variants, one sensitive to unoprostone and the other insensitive. We examined the effects of unoprostone on channel activity in excised inside-out patches and cell-attached patches. The half-maximal stimulation of the sensitive BK channels by Ca2+ was shifted from 3.4 ± 0.017 nM to 0.81 ± .0058 nM in the presence of 10 nM unoprostone. There was no effect on insensitive channels even at unoprostone concentrations as high as 1000 nM. There was no effect of unoprostone on the voltage dependence of the BK channels. Changes in open probability and effects of Ca2+ and unoprostone were best described by a synergistic binding model. These data would suggest that Ca2+ and unoprostone were binding to sites close to one another on the channel protein and that unoprostone binding causes the affinity of the calcium binding site to increase. This idea is consistent with three dimensional models of the Ca2+ binding site and a putative unoprostone binding domain. Our results have important implications for the clinical use of unoprostone to activate BK channels. Channel activation will be limited if intracellular Ca2+ is not elevated.

Copyright information:

© 2015 Elsevier B.V.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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