Synthesis, Solution Structure, And Phylum Selectivity Of A Spider Delta-Toxin That Slows Inactivation Of Specific Voltage-Gated Sodium Channel Subtypes
- Amer Soc Biochemistry Molecular Biology Inc
- Publication Type:
- Journal Article
- Journal Of Biological Chemistry, 2009, 284 (36), pp. 24568 - 24582
- Issue Date:
Magi 4, now renamed ?-hexatoxin-Mg1a, is a 43-residue neurotoxic peptide from the venom of the hexathelid Japanese funnel-web spider (Macrothele gigas) with homology to ?-hexatoxins from Australian funnel-web spiders. It binds with high affinity to receptor site 3 on insect voltage-gated sodium (NaV) channels but, unlike ?-hexatoxins, does not compete for the related site 3 in rat brain despite being previously shown to be lethal by intracranial injection. To elucidate differences in NaV channel selectivity, we have undertaken the first characterization of a peptide toxin on a broad range of mammalian and insect NaV channel subtypes showing that ?-hexatoxin-Mg1a selectively slows channel inactivation of mammalian NaV1.1, NaV1.3, and NaV1.6 but more importantly shows higher affinity for insect NaV1 (para) channels. Consequently, ?-hexatoxin-Mg1a induces tonic repetitive firing of nerve impulses in insect neurons accompanied by plateau potentials. In addition, we have chemically synthesized and folded ?-hexatoxin-Mg1a, ascertained the bonding pattern of the four disulfides, and determined its three-dimensional solution structure using NMR spectroscopy. Despite modest sequence homology, we show that key residues important for the activity of scorpion ?-toxins and ?-hexatoxins are distributed in a topologically similar manner in ?-hexatoxin-Mg1a. However, subtle differences in the toxin surfaces are important for the novel selectivity of ?-hexatoxin-Mg1a for certain mammalian and insect NaV channel subtypes. As such, ?-hexatoxin-Mg1a provides us with a specific tool with which to study channel structure and function and determinants for phylum- and tissue-specific activity.
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