Evaluation of gambierol and its analogs for their inhibition of human Kv1.2 and cytotoxicity
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Acknowledgments
The research studies were funded by the ERATO Murata Lipid Active Structure Project, Japan Science and Technology Agency, a Grant-in-Aid for Scientific Research on Innovative Areas ‘Chemical Biology of Natural Products’ from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan64 (M. S., and K. K.), and the Japan Society for the Promotion of Science for Funding Program for the Next Generation World-Leading Researchers (LS012) (M. Y. Y.).
We thank Takayuki Oka and
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2022, Food and Chemical ToxicologyCitation Excerpt :Gambierol is a polyether secondary metabolite produced by Gambierdiscus toxicus. Its main target are the voltage-gated potassium channels (Cuypers et al., 2008; Ghiaroni et al., 2005; Konoki et al., 2015; Rubiolo et al., 2015). In addition, gambierol has been demonstrated to activate sodium channels at higher concentrations, acting on the same site of the sodium channel as CTXs (Cagide et al., 2011; Inoue et al., 2003; Louzao et al., 2006).
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2020, NeuroscienceCitation Excerpt :As shown in Fig. 1, gambierol is characterized by a transfused octacyclic polyether core containing 18 stereogenic centers and a partially skipped triene side chain including a conjugated (Z,Z)-diene system. Gambierol and synthetic analogs in nanomolar concentrations have been reported to inhibit voltage-gated K+ (Kv) channels in various cells and tissues including mouse taste cells (Ghiaroni et al., 2005), Xenopus skeletal myocytes (Schlumberger et al., 2010), murine cerebellar neurons (Pérez et al., 2012), mammalian Kv1.1-Kv1.5 channels expressed in Xenopus oocytes or in Chinese hamster ovary (CHO) cells (Cuypers et al., 2008; Konoki et al., 2015), Kv3.1 channels expressed in mouse fibroblasts (Kopljar et al., 2009), and human Kv1.3 channels from T-lymphocytes (Rubiolo et al., 2015). In the range of nanomolar concentrations affecting Kv channels, gambierol has previously been reported to not affect or block voltage-gated Na+ channels (Ghiaroni et al., 2005; Cuypers et al., 2008; Schlumberger et al., 2010; Pérez et al., 2012).
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2018, ToxiconCitation Excerpt :In 2002 the total synthesis of gambierol was achieved (Fuwa et al., 2002). Studies with synthetic analogues of gambierol have demonstrated the importance of the structure and length of the polyether as well as the double bonds for toxic potency (Fuwa et al., 2003; Konoki et al., 2015; Rubiolo et al., 2015). There is very limited information about Gambierdiscus or Fukuyoa strain producers of gambierol.
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2016, ToxiconCitation Excerpt :Since gambierol is highly lipophilic the use of HEK293 cells instead of Xenopus oocytes is a likely explanation for the different response. Similarly, Kv1.2's gambierol affinity depends on the expression system used (Konoki et al., 2015). A valine substitution for T469 reduced, as expected, gambierol sensitivity (Fig. 1B–C).