Low Concentrations of Arsenite Target the Intraluminal Inositol 1, 4, 5-Trisphosphate Receptor/Ryanodine Receptor Crosstalk to Significantly Elevate Intracellular Ca 2 .

Arsenite is an established human carcinogen that induces cytotoxic and genotoxic effects through poorly defined mechanisms involving the formation of reactive oxygen species (ROS) and deregulated Ca ²⁺ homeostasis. We used variants of the U937 cell line to address the central issue of the mechanism whereby arsenite affects Ca ²⁺ homeostasis. We found that 6-hour exposure to the metalloid (2.5 μ M), although not associated with an immediate or delayed toxicity, causes a significant increase in the intracellular Ca ²⁺ concentration ([Ca ²⁺ ] _i ) through a mechanism characterized by the following components: 1) it was not affected by ROS produced under the same conditions; 2) a small amount of Ca ²⁺ was mobilized from the inositol-1,4,5-trisphosphate receptor (IP ₃ R), and this response was not augmented by greater concentrations of the metalloid; 3) large amounts of Ca ²⁺ were instead dose dependently mobilized from the ryanodine receptor (RyR) in response to IP ₃ R stimulation; 4) the cells maintained an intact responsiveness to agonist-stimulated Ca ²⁺ mobilization from both channels; 5) arsenite, even at 5-10 µ M, failed to directly mobilize Ca ²⁺ from the RyR; and 6) arsenite failed to enhance Ca ²⁺ release from the RyR under conditions in which the [Ca ²⁺ ] _i was increased by either RyR agonists or ionophore-stimulated Ca ²⁺ uptake. We therefore conclude that arsenite elevates the [Ca ²⁺ ] _i by directly targeting the IP ₃ R and its intraluminal crosstalk with the RyR. This mechanism likely mediates mitochondrial superoxide formation, downstream damage on various biomolecules (including genomic DNA), and mitochondrial dysfunction/apoptosis eventually occurring after longer incubation to, or exposure to greater concentrations of, arsenite.
(Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)