The stretch-activated channel blocker Gd(3+) reduces palytoxin toxicity in primary cultures of skeletal muscle cells

• Published in: Chemical research in toxicology 2012-09, Vol.25 (9), p.1912-20
• Main Authors: Del Favero, Giorgia, Florio, Chiara, Codan, Barbara, Sosa, Silvio, Poli, Mark, Sbaizero, Orfeo, Molgó, Jordi, Tubaro, Aurelia, Lorenzon, Paola
• Format: Article
• Language: English
• Subjects: Acrylamides - toxicity; Animals; Calcium - metabolism; Calcium Channel Blockers - chemistry; Calcium Channel Blockers - pharmacology; Calcium Channels - chemistry; Calcium Channels - metabolism; Cell Survival - drug effects; Cells, Cultured; Gadolinium - chemistry; Gadolinium - pharmacology; Life Sciences; Mice; Muscle, Skeletal - cytology; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Neurons and Cognition; Sodium-Calcium Exchanger - antagonists & inhibitors; Sodium-Calcium Exchanger - metabolism
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx300203x

Palytoxin (PLTX) is one of the most toxic seafood contaminants ever isolated. Reports of human food-borne poisoning ascribed to PLTX suggest skeletal muscle as a primary target site. Primary cultures of mouse skeletal muscle cells were used to study the relationship between Ca(2+) response triggered by PLTX and the development of myotoxic insult. Ca(2+) imaging experiments revealed that PLTX causes a transitory intracellular Ca(2+) response (transient phase) followed by a slower and more sustained Ca(2+) increase (long-lasting phase). The transient phase is due to Ca(2+) release from intracellular stores and entry through voltage-dependent channels and the Na(+)/Ca(2+) exchanger (reverse mode). The long-lasting phase is due to a massive and prolonged Ca(2+) influx from the extracellular compartment. Sulforhodamine B assay revealed that the long-lasting phase is the one responsible for the toxicity in skeletal muscle cells. Our data analyzed, for the first time, pathways of PLTX-induced Ca(2+) entry and their correlation with PLTX-induced toxicity in skeletal muscle cells. The cellular morphology changes induced by PLTX and the sensitivity to gadolinium suggest a role for stretch-activated channels.