The δ isomer of hexachlorocyclohexane induces rapid release of the myo-Inositol-1,4,5-trisphosphate-sensitive Ca²⁺ store and blocks capacitative Ca²⁺ entry in rat basophilic leukemia cells

Antigenic stimulation of rat basophilic leukemia cells releases Ca²⁺ from internal stores and increases membrane permeability to Ca²⁺. The δ isomer of hexachlorocyclohexane (δ-HCH) is structurally similar to myo-inositol-1,4,5-trisphosphate (IP₃) and is a potent releaser of stored Ca²⁺ from permeabilized cells. This release of Ca²⁺ is not mediated by a competitive interaction with the IP₃ receptor on the Ca²⁺ release channel on the endoplasmic reticulum. In intact cells, δ-HCH and, to a lesser extent, lindane (γ-hexachlorocyclohexane) transiently increase the intracellular Ca²⁺ concentration. The return to basal concentrations is mediated by the plasma membrane Ca²⁺ pumps and not by resequestration of Ca²⁺ into intracellular stores. Treatment of cells with δ-HCH (25-100 μM), but not lindane, leads to a progressive inhibition of the antigen- and thapsigargin-stimulated Ca²⁺ signal. Caffeine, a modulator of the ryanodine receptor Ca²⁺ channel, attenuates the rise in intracellular Ca²⁺ induced by δ-HCH, suggesting that ryanodine receptor-like Ca²⁺ channels may be present in RBL cells. At 25 μM δ-HCH, a concentration that does not inhibit the antigen-stimulated Ca²⁺ signal, the release of [³H]serotonin from antigen-stimulated cells is enhanced as is secretion of [³H]serotonin from cells pretreated with 25-100 μM lindane. The depletion of Ca²⁺ from intracellular stores by δ-HCH should evoke Ca²⁺ entry into the cells by a capacitative mechanism; however, divalent cation permeability across the plasma membrane (Mn²⁺ influx) is not increased but rather is decreased by δ-HCH. An understanding of the mechanism of action of δ-HCH in releasing stored Ca²⁺ and blocking Ca²⁺ influx across the plasma membrane may provide insights into the regulation of capacitative Ca²⁺ entry in nonexcitable cells.