The underlying mechanism of scorpion venom peptide BmK AS in reducing epilepsy seizures: mediated through dual modulation of Nav1.6 and the inflammasome pathway

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  The underlying mechanism of scorpion venom peptide BmK AS in reducing epilepsy seizures: mediated through dual modulation of Nav1.6 and the inflammasome pathway Abstract Introduction:  Voltage-gated sodium channel (VGSC) dysregulation, particularly of the Nav1.6 subtype, is a core mechanism underlying epileptogenesis and its associated neuropsychiatric comorbidities. The scorpion venom peptide BmK AS has demonstrated anticonvulsant potential, but its efficacy in chronic epilepsy and the precise mechanisms of action remain undefined. Methods:  Here, we show that BmK AS exerts robust anti-epileptic and neuroprotective effects through converging mechanisms. In a kainic acid-induced mouse model, BmK AS treatment reduced mortality and seizure parameters. Electrophysiological studies assessed BmK AS modulation of VGSC subtypes. The functional relevance of Nav1.6 targeting was confirmed by the loss of BmK AS’s anti-seizure efficacy upon its pharmacological blockade in a PTZ-in...

Modification of Closed-State Inactivation in Voltage-Gated Sodium Channel Nav1.7 by Two Novel Arachnid Toxins

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Modification of Closed-State Inactivation in Voltage-Gated Sodium Channel Nav1.7 by Two Novel Arachnid Toxins

Abstract

Venomous invertebrates have provided a large diversity of toxins that selectively and potently modulate ion channels that are indispensable tools for elucidating the structure and underlying mechanisms of these channels. Voltage-gated sodium channels (VGSC) are responsible for the initiation and propagation of action potentials in excitable cells and represent an important target for a variety of diseases. The Nav1.7 isoform, located in the peripheral nervous system, is central to pain signaling and is under intense investigation as a target for the treatment of pain. Closed-state inactivation (CSI) has been implicated in various disease states, such as arrhythmias and neuropathic pain. The investigation of venom toxins and VGSC CSI is poorly understood. However, many scorpion and spider toxins bind to site 3, characterized by a delay in steady-state inactivation, and interact with domain IV of the channel alpha subunit. In this study, two novel toxins were isolated from the venoms of Heteroctenus junceus and Poecilotheria regalis that demonstrated similar activity to site 3 modulators. Both toxins were shown to inhibit CSI while enhancing the rate at which CSI can occur. Taken together, this study demonstrates the need for additional investigation in CSI as well as the ability for toxins to modulate this phenomenon.

Johnson, J. W., Rikli, H. G., & Johnson, S. R. (2025). Modification of Closed-State Inactivation in Voltage-Gated Sodium Channel Nav1.7 by Two Novel Arachnid Toxins. Toxins, 17(9), 432. https://doi.org/10.3390/toxins17090432