A Structural Basis for Neuropathic Pain Syndromes Associated with Mutations in Nav1.7

Abstract

Voltage-gated sodium channels (Navs) are responsible for the upstroke of action potentials in electrically excitable cells. Transmission of nociceptive information from the body periphery to the central nervous system is mediated by specific isoforms of Navs present in dorsal root ganglion (DRG) and trigeminal ganglion (TG) sensory neurons. Nav1.7 is the most abundantly expressed isoform in DRG and TG neurons, and an isoleucine to valine mutation at residue 136 in the voltage- sensing domain (VSD) results in the disease, inherited erythromelalgia (IEM). From functional studies, it is clear that mutation at this residue results in increased Nav1.7 excitability, though the source of this hyperexcitability remains to be discovered. Here, we introduced a homologous isoleucine to valine mutation (residue 22) in the ancestral bacterial channel, NavAb, and present a X-ray crystallography structure of the mutant channel. Small shifts in the entire S1 segment and decreased interaction between residue 22 and charged arginine residues in the VSD were observed. This data supports a structural basis for the hyperexcitability of Nav1.7 associated with the IEM- causing mutation at residue 136.