Veratridine: A Janus-Faced Modulator of Voltage-Gated Sodium Ion Channels

Voltage-gated sodium ion channels (Na_Vs) are integral to both neuronal and muscular signaling and are a primary target for a number of proteinaceous and small molecule toxins. Included among these neurotoxins is veratridine (VTD), a C-nor-D homosteroidal alkaloid from the seeds of members of the Veratrum genus. VTD binds to Na_V within the pore region, causing a hyperpolarizing shift in the activation threshold in addition to reducing peak current. We have characterized the activity of VTD against heterologously expressed rat Na_V1.4 and have demonstrated that VTD acts on the channel as either an agonist or antagonist depending on the nature of the electrophysiological stimulation protocol. Structure-activity studies with VTD and VTD derivatives against Na_V mutants show that the functional duality of VTD can be decoupled. These findings suggest that the dichotomous activity of VTD may derive from two distinct, use-dependent binding orientations of the toxin.