These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: Low Concentrations of Arsenite Target the Intraluminal Inositol 1, 4, 5-Trisphosphate Receptor/Ryanodine Receptor Crosstalk to Significantly Elevate Intracellular Ca2.
    Author: Guidarelli A, Fiorani M, Cantoni O.
    Journal: J Pharmacol Exp Ther; 2018 Oct; 367(1):184-193. PubMed ID: 30068729.
    Abstract:
    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.
    [Abstract] [Full Text] [Related] [New Search]