BmK AEP, an Anti-Epileptic Peptide Distinctly Affects the Gating of Brain Subtypes of Voltage-Gated Sodium Channels

BmK AEP, a scorpion peptide purified form the venom of Buthus martensii Karsch, has been reported to display anti-epileptic activity. Voltage-gated sodium channels (VGSCs) are responsible for the rising phase of action potentials (APs) in neurons and, therefore, controlling neuronal excitability. To elucidate the potential molecular mechanisms responsible for its anti-epileptic activity, we examined the influence of BmK AEP on AP firing in cortical neurons and how BmK AEP influences brain subtypes of VGSCs (Na(v)1.1–1.3 and Na(v)1.6). BmK AEP concentration-dependently suppresses neuronal excitability (AP firing) in primary cultured cortical neurons. Consistent with its inhibitory effect on AP generation, BmK AEP inhibits Na(+) peak current in cortical neurons with an IC(50) value of 2.12 µM by shifting the half-maximal voltage of activation of VGSC to hyperpolarized direction by ~7.83 mV without affecting the steady-state inactivation. Similar to its action on Na(+) currents in cortical neurons, BmK AEP concentration-dependently suppresses the Na(+) currents of Na(v)1.1, Na(v)1.3, and Na(v)1.6, which were heterologously expressed in HEK-293 cells, with IC(50) values of 3.20, 1.46, and 0.39 µM with maximum inhibition of 82%, 56%, and 93%, respectively. BmK AEP shifts the voltage-dependent activation in the hyperpolarized direction by ~15.60 mV, ~9.97 mV, and ~6.73 mV in Na(v)1.1, Na(v)1.3, and Na(v)1.6, respectively, with minimal effect on steady-state inactivation. In contrast, BmK AEP minimally suppresses Na(v)1.2 currents (~15%) but delays the inactivation of the channel with an IC(50) value of 1.69 µM. Considered together, these data demonstrate that BmK AEP is a relatively selective Na(v)1.6 gating modifier which distinctly affects the gating of brain subtypes of VGSCs.