title: The ICl,swell inhibitor DCPIB blocks Kir channels that possess weak affinity for PIP2.
abstract: Inwardly rectifying K(+) (Kir) channels are important contributors to the resting membrane potential and regulate cellular excitability. The activity of Kir channels depends critically on the phospholipid PIP2. Several modulators of the activity of Kir channels alter the apparent affinity of the channel to PIP2. Channels with high apparent affinity to PIP2 may not respond to a given modulator, but mutations that decrease such affinity can render the channel susceptible to modulation. Here, we identify a known inhibitor of the swelling-activated Cl(-) current, DCPIB, as an effective inhibitor of a number of Kir channels both in native cardiac cells and in heterologous expression systems. We show that the apparent affinity to PIP2 determines whether DCPIB will serve as an efficient blocker of Kir channels. These effects are consistent with a model in which DCPIB competes with PIP2 for a common binding site.
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.|Department of Anesthesiology, Boston University, Boston, MA, 02118, USA.
authors.forename: Wu
authors.initials: W
authors.lastname: Deng
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Mahajan
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.
authors.forename: Clive M
authors.initials: CM
authors.lastname: Baumgarten
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA. delogothetis@vcu.edu.
authors.forename: Diomedes E
authors.initials: DE
authors.lastname: Logothetis
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D018118:Chloride Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003517:Cyclopentanes / Q000494:pharmacology*; D007189:Indans / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000187:drug effects; D011817:Rabbits; D014981:Xenopus
chemical_list: C443139:4-(2-butyl-6,7-dichlor-2-cyclopentyl-indan-1-one-5-yl)oxybutyric acid; D018118:Chloride Channels; D003517:Cyclopentanes; D007189:Indans; D019269:Phosphatidylinositol 4,5-Diphosphate; D024661:Potassium Channels, Inwardly Rectifying
keywords: DCPIB; Kir channels; PIP2; Patch clamp; Two-electrode voltage clamp
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