A Buthus martensii Karsch scorpion sting targets Na_v1.7 in mice and mimics a phenotype of human chronic pain

Abstract

Gain-of-function and loss-of-function mutations in Na_v1.7 cause chronic pain and pain insensitivity, respectively. The preferential expression of Na_v1.7 in the peripheral nervous system and its role in human pain signaling make Na_v1.7 a promising target for next-generation pain therapeutics. However, pharmacological agents have not fully recapitulated these pain phenotypes, and because of the lack of subtype-selective molecular modulators, the role of Na_v1.7 in the perception of pain remains poorly understood. Scorpion venom is an excellent source of bioactive peptides that modulate various ion channels, including voltage-gated sodium (Na_v) channels. Here, we demonstrate that Buthus martensii Karsch scorpion venom (BV) elicits pain responses in mice through direct enhancement of Na_v1.7 activity and have identified Makatoxin-3, an α-like toxin, as a critical component for BV-mediated effects on Na_v1.7. Blocking other Na_v subtypes did not eliminate BV-evoked pain responses, supporting the pivotal role of Na_v1.7 in BV-induced pain. Makatoxin-3 acts on the S3–S4 loop of voltage sensor domain IV (VSD₄) of Na_v1.7, which causes a hyperpolarizing shift in the steady-state fast inactivation and impairs inactivation kinetics. We also determined the key residues and structure–function relationships for the toxin–channel interactions, which are distinct from those of other well-studied α toxins. This study not only reveals a new mechanism underlying BV-evoked pain but also enriches our knowledge of key structural elements of scorpion toxins that are pivotal for toxin–Na_v1.7 interactions, which facilitates the design of novel Na_v1.7 selective modulators.

In Brief

This study establishes Na_v 1.7 as primarily responsible for Buthus martensii Karsch scorpion sting–evoked pain and sheds new insights into the development of Na_v1.7-selective modulators.