Brevenal prevents ciguatoxin and brevetoxin activation of NaV channels
Résumé
The voltage-gated sodium channel (Nav channel) is the target of numerous neurotoxins. Among them, phycotoxins like ciguatoxins (CTXs) or brevetoxins (PbTXs) exert deleterious effects on Nav channels, frequently inducing human food intoxication in Pacific, Caribbean and Indian areas termed ciguatera or neurotoxic shellfish poisoning respectively, for which there is no specific treatment. Brevenal, a metabolite produced by the dinoflagellate Karenia brevis, has been shown to compete with PbTXs over Nav channels on an unknown molecular site. We hypothesized that brevenal may counteract the effects of PbTXs and CTXs on Nav channels. We showed that brevenal did not modify the biophysical properties of the rat brain Nav1.2 channel expressed in Xenopus oocytes, using the two-electrode voltage clamp technique. Moreover, brevenal antagonized the effet of PbTx-2 on Na+ currents mediated by Nav1.2 channel. To further characterize the pharmacological properties of brevenal, we measured its effects on the calcium response induced by PbTx-2 and P-CTX-1B in the rat pituitary GH3b6 cell line, which expresses several Nav channels. Our results show that PbTX-2- and P-CTX-1B- evoked Nav channel activation induces TTX-sensitive transient increase of intracellular Ca2+. Brevenal (1 and 10 μM) antagonizes PbTX-2- and P-CTX-1B- evoked calcium response in GH3b6 cells. Altogether, our findings suggest that brevenal binds silently to Nav channels and thereby antagonized CTX and PbTX effects. This in vitro proof of concept allows us to consider the therapeutic development of natural molecules such as brevenal for the management of toxin-induced channlopathies linked to Nav channels.
