Inhibition of Sodium Ion Channel Function with Truncated Forms of Batrachotoxin

Abstract

A novel family of small molecule inhibitors of voltage-gated sodium channels (Navs) based on the structure of batrachotoxin (BTX) – a well-known channel agonist – is described. Protein mutagenesis and electrophysiology experiments reveal the binding site as the inner pore region of the channel, analogous to BTX, alkaloid toxins, and local anesthetics. Homology modeling of the eukaryotic channel based on recent crystallographic analyses of bacterial NaVs suggests a mechanism of action for ion conduction block.

Batrachotoxin acts as a stent to hold open homotetrameric prokaryotic voltage-gated sodium channels

“…Ultimately, BTX acts as a NavBac activator, because its stabilization of conducting states functionally outweighs its limited blocking action. Du Bois and collaborators show clearly that small molecules based on the BTX structure can act as potent Nav inhibitors, despite their molecular heritage (Logan et al, 2016; Toma et al, 2016). Extension of these studies, including further experiments with additional use-dependent modulators (Lee et al, 2012a,b; Ahern et al, 2016), should pave the way for a deeper understanding of mechanisms of both excitatory and inhibitory modulation and may uncover new applications for use-dependent Nav-targeted ligands.…”

Single rat muscle Na + channel mutation confers batrachotoxin autoresistance found in poison-dart frog Phyllobates terribilis

“…notion that functional constraint shapes the evolution of the P. terribilis Nav1.4 inner cavity (9). Recently, two reports from the Du Bois' laboratory described the organic syntheses of various BTX analogs and enantiomeric BTX toxins (17,18). These authors discovered a family of BTX analogs and nonnatural (+)-BTX toxins as reversible channel blockers.…”

The pharmacology of voltage-gated sodium channel activators

“…The binding site of batrachotoxin is located within the inner pore region, with single point mutations of amino acids located on S6 in DI (I433, N434, L437), DII (N784, L788), DIII (F1236, S1276, L1280) and DIV (F1579, N1584) causing rNa V 1.4 to become insensitive to the effects of batrachotoxin (Figure 4-8) (Toma et al, 2016;Wang et al, 2001;Wang et al, 2000b;Wang, 1998, 1999). These amino acids are conserved on hNa V 1.1-1.8, accounting for the limited selectivity of batrachotoxin for Na V channels.…”