Recombinant Heteroscodra maculata Delta-theraphotoxin-Hm1a

Function

Gating-modifier toxin that potently inhibits inactivation of the mammalian Nav1.1/SCN1A sodium channel (EC(50)=38 nM) (PubMed:27281198, PubMed:30076230). Also moderately inhibits inactivation of Nav1.2/SCN2A (EC(50)=236 nM) and Nav1.3/SCN3A (EC(50)=220 nM) when the channels are expressed in oocytes without the beta-1 auxiliary subunit (PubMed:27281198). Does not inhibit inactivation of Nav1.2/SCN2A when the channel is coexpressed with the beta-1 auxiliary subunit (PubMed:30076230). When tested on Nav1.1/SCN1A channel, it enhances peak current amplitude and potently delays channel inactivation in a dose-dependent manner, leading to a large sustained current (PubMed:30076230). It has no effect on the voltage-dependence of steady-state activation, and induces a depolarizing shift in the voltage dependence of inactivation (PubMed:30076230). In addition, it does not modify the recovery from fast inactivation in Nav1.1/SCN1A (PubMed:30076230). The binding affinity and subtype selectivity of the toxin towards Nav1.1/SCN1A channel is determined by residues within both the S1-S2 and S3-S4 loops of the domain IV voltage sensor of the channel (PubMed:27281198). This toxin also weakly inhibits several subtypes of voltage-gated potassium channels (PubMed:27281198). It moderately blocks Kv2.1/KCNB1 (23% inhibition at 100 nM), Kv2.2/KCNB2 (19.7% at 100 nM and 51% at 300 nM), Kv4.1/KCND1 (IC(50)=280 nM), Kv4.2/KCND2 (39% at 300 nM) and Kv4.3/KCND3 (43% at 300 nM) (PubMed:12065754). In vivo, intracerebroventricular injection into mice elicits convulsions, spasms, tremors and rapid death (PubMed:12065754). When injected into mouse hindpaw, the toxin elicits an immediate and robust response to pain (PubMed:27281198). However, intraplantar injection of toxin does not cause neurogenic inflammation or alter sensitivity to heat, indicative of a modality-specific effect on mechanosensitive neurons (PubMed:27281198). In Dravet syndrome mice model, intracerebroventricular infusion of this peptide rescues mice from seizures and premature death (PubMed:30076230)