Mechanisms of δ-hexachlorocyclohexane toxicity: II. Evidence for Ca2+-dependent K+-selective ionophore activity

Edmond D. Buck, Isaac N Pessah

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

δ-Hexachlorocyclohexane (δ-HCH) interacts with cardiac ryanodine- sensitive Ca2+ channels (RyR2), accounting in part for altered Ca2+ transients and contractility (reported in companion report). Analysis of channel gating kinetics in the presence of δ-HCH also revealed a nonfluctuating membrane current that remained even after RyR2 channels were blocked. We further elucidated the nature of a direct interaction between δ- HCH and biological membranes by meaSUring ionic currents across planar lipid bilayers made from defined lipids lacking cellular protein using voltage- clamp. Dimethyl sulfoxide, in the presence or absence of 50 μM γ-HCH (lindane) or δ-HCH, produced negligible steady-state current with symmetric 100 mM CsCl in the range of ±50 mV. However, the addition of 50 μM Ca2+ to the bilayer chamber in the presence of δ-HCH induced a profound increase in ionic permeability that was not seen in the presence of γ-HCH or dimethyl surfoxide control. Significantly, the permeability increase 1) was proportional with increasing Ca2+ to ~600 μM and saturated between 1 and 2 mM Ca2+ regardless of holding potential, 2) occurred only when δ-HCH and Ca2+ were added to the same side of the membrane, and 3) was independent of the order of addition or of the side of the membrane to which δ-HCH and Ca2+ was added. The Ca2+-dependent current produced by δ-HCH was highly selective for monovalent cations (K+ >> Cs+ > Na+), with negligible conductance for Ca2+ or Cl-. In symmetric 100 mM K+, the conductance induced with 50 μM concentration each of δ-HCH and Ca2+ was 4.25 pA/mV. The results show that δ-HCH increases the ionic permeability of phospholipid membranes by two distinct Ca2+-dependent mechanisms: one mediated through RyR and the other mediated by a unique ionophore activity.

Original languageEnglish (US)
Pages (from-to)486-493
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume289
Issue number1
StatePublished - 1999

ASJC Scopus subject areas

  • Pharmacology

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