257 Original Paper Cell Physiol Biochem 2006;17:257-268 Accepted: April 05, 2006 Cellular Physiology Cellular Physiology Cellular Physiology Cellular Physiology Cellular Physiology and Biochemistr and Biochemistr and Biochemistr and Biochemistr and Biochemistry Copyright © 2006 S. Karger AG, Basel Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com © 2006 S. Karger AG, Basel 1015-8987/06/0175-0257$23.50/0 Accessible online at: www.karger.com/journals/net The Sodium Channel of Human Excitable Cells is a Target for Gambierol M. Carmen Louzao 1 , Eva Cagide 1 , Mercedes R. Vieytes 2 , Makoto Sasaki 3 , Haruhiko Fuwa 3 , Takeshi Yasumoto 4 and Luis M. Botana 1 1 Departamento de Farmacologia, 2 Departamento de Fisiologia Animal. Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, 3 Graduate School of Life Sciences, Tohoku University, 4 Japan Food Research Laboratories, Tama Laboratory, Tokyo Luis M. Botana Departamento de Farmacologia, Facultad de Veterinaria Universidad de Santiago de Compostela 27002 Lugo (Spain) Tel & Fax -+34 982 252 242, E-Mail ffbotana@lugo.usc.es Key Words Sodium channel  Gambierol  Neuroblastoma Abstract Background: Gambierol is a polycyclic ether toxin with the same biogenetic origin as ciguatoxins. Gambierol has been associated with neurological symptoms in humans even though its mechanism of action has not been fully characterized. Methods: We studied the effect of gambierol in human neuroblastoma cells by using bis-oxonol to measure membrane potential and FURA-2 to monitor intracellular calcium. Results: We found that this toxin: i) produced a membrane depolarization, ii) potentiated the effect of veratridine on membrane potential iii) decreased ciguatoxin- induced depolarization and iv) increased cytosolic calcium in neuroblastoma cells. Conclusion: These results indicate that gambierol modulate ion fluxes by acting as a partial agonist of sodium channels. Introduction In the last years there has been an explosion of interest in biologically active natural products of marine origin [1-4]. Polycyclic ethers class of marine natural products (exemplified by brevetoxins (PbTXs), ciguatoxins (CTXs), maitotoxin and recently gambierol) are particularly attractive for chemists, due to their structural novelty and toxicity [3, 5]. The target receptor has only been identified for PbTXs and CTXs, mainly because of the extremely limited availability of those toxins from natural sources [6]. PbTXs and CTXs exert their neurotoxicity by association with a specific binding site on the voltage-gated sodium channels of excitable membranes, designed as site 5 [7-12]. Toxin binding alters the channel’s function in two ways: (1) the activation voltage for channel opening shifts to a more negative value and (2) the inactivation of opened channels is inhibited, resulting in persistent activation [11, 13]. Despite the common polycyclic structure, all those toxins show diverse biological activities with extreme Downloaded by: 54.211.133.135 - 9/14/2016 12:16:45 AM