Tarantula Toxin SGTx-1 alters Gating Kinetics of Human Voltage-Gated Sodium Channel Nav1.7

Abstract

Voltage-gated sodium (Nav) channels play a key role in action potential generation in excitable cells and are targets of invertebrate toxins and therapeutics. The tarantula toxin SGTx-1 has been shown to target the domain IV voltage sensor (VSDIV) of Nav1.2, prolonging the macroscopic sodium current elicited during whole-cell voltage clamp experiments. We demonstrate that SGTx-1 has a similar effect on human Nav1.7 (hNav1.7) expressed in tsa-201 cells, with an apparent affinity in the low micromolar range. To better understand the molecular mechanism of toxin action, we are using Rosetta molecular modeling software to develop homology models of resting and activated states of the hNav1.7-VSDIV. The models are based on the crystal structures of an hNav1.7-NavAb chimera, NavAb, and the two-pore cation channel (TPC1) from Arabidopsis. Using RosettaDock, we have modeled the proposed binding site of SGTx-1 with the hNav1.7-VSDIV in multiple states. We hypothesize that SGTx-1 binds a resting state of the VSDIV, and thus prevents channel fast-inactivation and prolongs induced macroscopic current. We identify potential interactions that could allow the toxin to exert its influence on channel activity. An understanding of the basic molecular mechanism of SGTx-1 interaction with hNav1.7-VSDIV may inform the rational design of novel therapeutics targeting Nav channels.