Brevetoxin versus Brevenal Modulation of Human Nav1 Channels

Brevetoxins (PbTx) and brevenal are marine ladder-frame polyethers. PbTx binds to activates voltage-gated sodium (Nav) channels in native tissues, whereas antagonizes these actions. However, the effects of on recombinant Nav channel function have not been systematically analyzed. In this study, PbTx-3 modulation tissue-representative subtypes Nav1.2, Nav1.4, Nav1.5, Nav1.7 were examined using automated patch-clamp. While elicit concentration-dependent subtype-specific modulatory effects, is >1000-fold more potent than brevenal. Consistent with observed Nav1.2 Nav1.4 PbTx-3- brevenal-sensitive, Nav1.5 appeared resistant. Interestingly, incorporation intracellular solution caused become less sensitive Furthermore, we generated a computational model PbTx-2 bound lipid-exposed side interface between domains I IV Nav1.2. Our results consistent competitive antagonism brevetoxins brevenal, setting basis for future mutational analyses channels’ interaction findings provide valuable insights into functional by which may implications development new modulators potential therapeutic applications.