This lethal neurotoxin (without cyclization at position 53) inhibits neuronal voltage-gated sodium channel Nav1.2/SCN2A (IC(50)=10-150 nM), rNav1.3/SCN3A (IC(50)=338 nM), Nav1.6/SCN8A (IC(50)=117 nM), and hNav1.7/SCN9A (IC(50)=9.6-33 nM) (PubMed:18628201, PubMed:20855463, PubMed:25658507, PubMed:29703751,PubMed:31234412, PubMed:23760503). It inhibits activation of sodium channel by trapping the voltage sensor of domain II (DIIS4) in the closed configuration (PubMed:18628201, PubMed:23760503). The toxin neither shifts the Nav1.7/SCN9A activation curve nor modifies the slope factor (PubMed:20855463). It does not slow fast-inactivation of hNav1.7/SCN9A channels (PubMed:20855463). In addition, it has only a weak affinity for lipid membranes (PubMed:18054060, PubMed:29703751, PubMed:28115115). This toxin also exists with a pyroglutamate at position 53 (PubMed:23826086). The sole difference observed between modified (mHwTx-IV) and unmodified toxins is that moderate or high depolarization voltages (200 mV) permit the unmodified toxin to dissociate, whereas mHwTx-IV toxin does not dissociate, even at high depolarization voltages (PubMed:23826086). These data indicate that mHwTx-IV strongly binds to voltage sensor of sodium channel even at extreme depolarization voltages (PubMed:23826086). Expressed by the venom gland. The presence of a 'disulfide through disulfide knot' structurally defines this protein as a knottin. Two forms of huwentoxin-IV exist in the venom of H.schmidti, a non-N-terminally modified (HwTx-IV) and a naturally modified peptide with pyroglutamic acid residue at position 53 (mHwTx-IV). mHwTx-IV shows no observable difference with the unmodified toxin when applied to the TTX-S sodium channel of DRG neuron (IC(50)~50 nM) or when tested on hNav1.7/SCN9A (IC(50)=30.8 nM) (PubMed:23826086, PubMed:28115115). In addition, similarly to the unmodified toxin, mHwTx-IV has only a weak affinity for lipid membranes (PubMed:28115115). However, in contrast with HwTx-IV, which dissociates at moderate and high depolarization voltages (50-200 mV), mHwTx-IV inhibition of TTX-sensitive sodium channels is not reversed by strong depolarization voltages (PubMed:23826086). mhuwentoxin-IV (with pyrrolidone carboxylic acid (Glu) at position 53). huwentoxin-IV (with unmodified Glu at position 53). huwentoxin-IV (with unmodified Glu at position 53). Shows a weak or no inhibition on rNav1.4/SCN4A (IC(50)=3.9->10 uM) and hNav1.5/SCN5A sodium channels (IC(50)=>10-25 uM) (PubMed:18628201, PubMed:25658507). This toxin has also been shown to weakly inhibit Kv11.1/KCNH2/ERG1, Kv1.2/KCNA2 and Kv1.3/KCNA3 (PubMed:29483648). Belongs to the neurotoxin 10 (Hwtx-1) family. 22 (Htx-4) subfamily.