8.B.5.3.7
ω-grammotoxin, SIA. Blocks P/Q type voltage-dependent calcium channels, Ca_v2.1 (Ono et al., 2011).  ω-Grammotoxin-SIA (GrTX-SIA) was originally isolated from the venom of the Chilean rose tarantula and shown to function as a gating modifier of voltage-gated Ca2+ (CaV) channels.  It also inhibits voltage-gated K⁺ (KV) channel currents via a similar mechanism that involved binding to a conserved S3-S4 region in the voltage-sensing domains (VSDs). Since voltage-gated Na⁺ (NaV) channels contain homologous structural motifs, It might also inhibit members of this ion channel family as well. Collaço et al. 2024 showed that GrTX-SIA can impede the gating process of multiple NaV channel subtypes with NaV1.6 being the most susceptible target. Molecular docking of GrTX-SIA onto NaV1.6, supported by a p.E1607K mutation, revealed the voltage sensor in domain IV (VSDIV) as  a primary site of action. The biphasic manner in which current inhibition appeared to occur suggested a second, possibly lower-sensitivity binding locus, which was identified as VSDII by using KV2.1/NaV1.6 chimeric voltage-sensor constructs. Subsequently, the NaV1.6p.E782K/p.E838K (VSDII), NaV1.6p.E1607K (VSDIV), and particularly the combined VSDII/VSDIV mutant lost virtually all susceptibility to GrTX-SIA. Together with existing literature, these results suggest that GrTX-SIA recognizes modules in NaV channel VSDs that are conserved among ion channel families, thereby allowing it to act as a comprehensive ion channel gating modifier peptide (Collaço et al. 2024).