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

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 Na_v1.7 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 <i>Heteroctenus junceus</i> and <i>Poecilotheria regalis</i> 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.