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Marine Algal Toxin Azaspiracid Is an Open-State Blocker of hERG Potassium Channels

Author(s): Twiner, M.J.; G.J. Doucette; A. Rasky; X-P. Huang; B.L. Roth; M.C. Sanguinetti


Publication Type: Journal Article

Journal Title: Chemical Research in Toxicology

Date of Publication: 2012

Reference Information: 25(9): 1975-1984

Keywords: azaspiracids; cytotoxicity; harmful algal blooms; hERG potassium channels; marine algal biotoxins

Abstract: Azaspiracids (AZA) are polyether marine dinoflagellate toxins that accumulate in shellfish and represent an emerging human health risk. Although human exposure is primarily manifested by severe and protracted diarrhea, this toxin class has been shown to be highly cytotoxic, a teratogen to developing fish, and a possible carcinogen in mice. Until now, AZA’s molecular target has not yet been determined. Using three independent methods (voltage clamp, channel binding assay, and thallium flux assay), we have for the first time demonstrated that AZA1, AZA2, and AZA3 each bind to and block the hERG (human ethera`-go-go related gene) potassium channel heterologously expressed in HEK-293 mammalian cells. Inhibition of K+ current for each AZA analogue was concentration-dependent (IC50 value range: 0.64-0.84 µM). The mechanism of hERG channel inhibition by AZA1 was investigated further in Xenopus oocytes where it was shown to be an open-state-dependent blocker and, using mutant channels, to interact with F656 but not with Y652 within the S6 transmembrane domain that forms the channel’s central pore. AZA1, AZA2, and AZA3 were each shown to inhibit [3H]dofetilide binding to the hERG channel and thallium ion flux through the channel (IC50 value range: 2.1-6.6 µM). AZA1 did not block the K+ current of the closely related EAG1 channel. Collectively, these data suggest that the AZAs physically block the K+ conductance pathway of hERG1 channels by occluding the cytoplasmic mouth of the open pore. Although the concentrations necessary to block hERG channels are relatively high, AZAinduced blockage may prove to contribute to the toxicological properties of the AZAs.