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Na + /K + ‐ATPase inhibitor palytoxin enhances vulnerability of cultured cerebellar neurons to domoic acid via sodium‐dependent mechanisms
Author(s) -
PérezGómez Anabel,
Novelli Antonello,
FernándezSánchez M. Teresa
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2010.06602.x
Subject(s) - excitotoxicity , domoic acid , nmda receptor , okadaic acid , neurotoxicity , chemistry , kainic acid , biochemistry , pharmacology , endocrinology , medicine , biophysics , biology , glutamate receptor , receptor , toxicity , enzyme , toxin , phosphatase
J. Neurochem. (2010) 114 , 28–38. Abstract Dysfunction or deficiency of the Na + /K + ‐ATPase appears to be a common event in a variety of pathological conditions in the central nervous system. Studies on neurotoxicity associated to impaired Na + /K + ‐ATPase activity have focused on NMDA receptors, while the involvement of non‐NMDA receptors has been much less explored. We show that mild, non‐toxic, exposures to the Na + /K + ‐ATPase inhibitor palytoxin (PTX) synergistically sensitized the vulnerability of neurons to normally non‐toxic concentrations of domoic acid, leaving NMDA receptor‐mediated excitotoxic response unaltered. Enhancement of excitotoxicity required at least 1 h pre‐exposure to PTX, was not observed after longer exposures to PTX, and did not require RNA synthesis. PTX caused a voltage‐sensitive Na + channel‐independent increase in intracellular Na + . Both intracellular Na + increase and potentiation of excitotoxicity depended upon the external concentrations of Na + and Cl − , and were suppressed by the anion exchanger blocker 4,4′‐diisothiocyanatostilbene‐2, 2′‐disulfonic acid in a dose‐dependent manner. Other stilbene derivatives, chloride channel antagonists or Na + cotransporter inhibitors proved ineffective. Our results demonstrate a crucial role for Na + /K + ‐ATPase activity in determining neuronal vulnerability to domoic acid‐mediated excitotoxicity. They also raise reasonable concern about possible risks for human health associated to the ingestion of low amounts of phycotoxins PTX and domoic acid in food.