TY - JOUR T1 - Low Concentrations of Arsenite Target the Intraluminal Inositol 1, 4, 5-Trisphosphate Receptor/Ryanodine Receptor Crosstalk to Significantly Elevate Intracellular Ca<sup>2+</sup> JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 184 LP - 193 DO - 10.1124/jpet.118.250480 VL - 367 IS - 1 AU - Andrea Guidarelli AU - Mara Fiorani AU - Orazio Cantoni Y1 - 2018/10/01 UR - http://jpet.aspetjournals.org/content/367/1/184.abstract N2 - 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 Ca2+ homeostasis. We used variants of the U937 cell line to address the central issue of the mechanism whereby arsenite affects Ca2+ homeostasis. We found that 6-hour exposure to the metalloid (2.5 μM), although not associated with an immediate or delayed toxicity, causes a significant increase in the intracellular Ca2+ concentration ([Ca2+]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 Ca2+ was mobilized from the inositol-1,4,5-trisphosphate receptor (IP3R), and this response was not augmented by greater concentrations of the metalloid; 3) large amounts of Ca2+ were instead dose dependently mobilized from the ryanodine receptor (RyR) in response to IP3R stimulation; 4) the cells maintained an intact responsiveness to agonist-stimulated Ca2+ mobilization from both channels; 5) arsenite, even at 5–10 µM, failed to directly mobilize Ca2+ from the RyR; and 6) arsenite failed to enhance Ca2+ release from the RyR under conditions in which the [Ca2+]i was increased by either RyR agonists or ionophore-stimulated Ca2+ uptake. We therefore conclude that arsenite elevates the [Ca2+]i by directly targeting the IP3R 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. ER -