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 (Nav1.1–1.3 and Nav1.6). 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 IC50 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 Nav1.1, Nav1.3, and Nav1.6, which were heterologously expressed in HEK-293 cells, with IC50 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 Nav1.1, Nav1.3, and Nav1.6, respectively, with minimal effect on steady-state inactivation. In contrast, BmK AEP minimally suppresses Nav1.2 currents (~15%) but delays the inactivation of the channel with an IC50 value of 1.69 µM. Considered together, these data demonstrate that BmK AEP is a relatively selective Nav1.6 gating modifier which distinctly affects the gating of brain subtypes of VGSCs.
Nitrergic modulation of neuronal excitability in the mouse hippocampus is mediated via regulation of Kv2 and voltage‐gated sodium channels
