δ-buthitoxin-Hj2a (Hj2a) is a peptidyl toxin originally isolated from the venom of the scorpion, Hottentotta jayakari. Hj2a acts as a voltage-gated sodium (Na_v) 1.1 channel activator, but it also harbors promiscuous activity towards multiple human Na_V channel subtypes. Hj2a is unique in that it exhibits a dual α/β mode of action by modifying both the inactivation (α-toxin activity) and activation (β-toxin activity) properties of the Na_V1.1 channel¹.

Na_V channels are involved in a wide array of physiological processes and play a fundamental role in normal neurological function, especially in the initiation and propagation of action potentials. In particular, the Na_V1.1 channel is predominantly expressed in inhibitory interneurons of the brain and it plays a major role in regulating brain rhythms and cognitive functions. Mutations in the Na_V1.1 channel were shown to be associated with Dravet syndrome (DS), a severe form of pediatric epilepsy. Selective modulators of the Na_V1.1 channel can be useful therapeutics for DS treatment since they target the underlying molecular deficit. The unusual dual mode of action of Hj2a provides an alternative approach for the development of selective Na_V1.1 channel modulators for the treatment of DS^1,2.