6ena

Structural highlights

Function

NEMA1_LINLO Highly potent toxin against insect sodium channel (Nav) and with less potent activity against mammalian sodium channels (PubMed:29567943). Potently inhibits inactivation of insect sodium channels of B.germanica (BgNav1) (EC(50)=8.6 nM), D.melanogaster (DmNav1), and arachnid sodium channel V.destructor (VdNav1) (PubMed:29567943, PubMed:34445875). Also delays the inactivation of most mammalian Nav channels tested (hNav1.1/SCN1A; EC(50)=124.1 nM, rNav1.2/SCN2A; EC(50)=359.6 nM, rNav1.3/SCN3A; EC(50)=135.4 nM, rNav1.4/SCN4A; EC(50)=145.5 nM, hNav1.5/SCN5A; EC(50)=138.3 nM, mNav1.6/SCN8A; EC(50)=240.4 nM, hNav1.9/SCN9A; EC(50)=76.5 nM) (PubMed:29567943, PubMed:34445875). 1 uM is enough to completely inhibits the inactivation, resulting in sustained non-inactivating currents (PubMed:29567943). In addition, the toxin significantly enhances the recovery from inactivation, and the open state is not required for the toxin to interact with the channel (PubMed:29567943). In vivo, injection into green crabs (Carcinus maenas at 1 mug/kg) of small doses (1-5 ug/kg) results in slow and fast permanent paralysis, whereas injection of high doses (more than 10 ug/kg) causes death (PubMed:29567943). Injection into juvenile Blaptica dubia cockroaches results in death or permanent paralysis at doses higher than 7.1 ug/kg (PubMed:29567943). Injection into brine shrimp (Artemia salina) stops movement or causes death after 24 hours (EC(50)=0.3 uM) (PubMed:34445875). In the rare inherited cardiac arrhythmia Brugada syndrome 1 (BRGDA1), this toxin is able to restore the loss of function by reducing channel inactivation, without affecting activation, by binding to Nav1.5/SCN5A (PubMed:32850980).^{[1] [2] [3]}

References

1. ↑ Jacobsson E, Andersson HS, Strand M, Peigneur S, Eriksson C, Lodén H, Shariatgorji M, Andrén PE, Lebbe EKM, Rosengren KJ, Tytgat J, Göransson U. Peptide ion channel toxins from the bootlace worm, the longest animal on Earth. Sci Rep. 2018 Mar 22;8(1):4596. PMID:29567943 doi:10.1038/s41598-018-22305-w
2. ↑ Nijak A, Labro AJ, De Wilde H, Dewals W, Peigneur S, Tytgat J, Snyders D, Sieliwonczyk E, Simons E, Van Craenenbroeck E, Schepers D, Van Laer L, Saenen J, Loeys B, Alaerts M. Compound Heterozygous SCN5A Mutations in Severe Sodium Channelopathy With Brugada Syndrome: A Case Report. Front Cardiovasc Med. 2020 Jul 24;7:117. PMID:32850980 doi:10.3389/fcvm.2020.00117
3. ↑ Jacobsson E, Peigneur S, Andersson HS, Laborde Q, Strand M, Tytgat J, Göransson U. Functional Characterization of the Nemertide α Family of Peptide Toxins. J Nat Prod. 2021 Aug 27;84(8):2121-2128. PMID:34445875 doi:10.1021/acs.jnatprod.1c00104