Pompilidotoxins: Novel Peptide Neurotoxins Blocking Sodium Channel Inactivation from Solitary Wasp Venom

Katsuhiro      Konnoa; Nobufumi      Kawai

Abstract

Solitary wasps are known to inject their venoms into insects or spiders and paralyze the prey to feed their larvae. Therefore, the solitary wasp venoms should contain a variety of components acting on nervous systems. Until recently, however, only a few solitary wasp venoms have been studied. We have surveyed bioactive substances in solitary wasp venoms and recently found novel peptide neurotoxins, α- and β-pompilidotoxins (α- and β-PMTXs), in the venoms of pompilid wasps. Chemical and pharmacological characterization of PMTXs revealed that they are small peptides consisting of 13 amino acids with no disulfide bonds. Structure-activity relationship studies showed that the basic amino acid at positions 1, 3 and 12 are essential for regulating the activity. PMTXs facilitate neurotransmission both at invertebrate neuromuscular junctions and in mammalian central synapses by repetitive firings in the presynaptic axons. Whole cell recordings from rat trigeminal ganglion neurons and cultured hippocampal neurons revealed that PMTXs slowed Na+ channel inactivation without affecting kinetics of Na+ channel activation. These effects are similar to those of sea anemone toxins or scorpion toxins, but the PMTXs are distinct from these known toxins in their mode of action. We found region-specific distribution of PMTX-sensitive Na+ channels in the central nervous system by investigating the synaptic transmission in the hippocampal slice preparation and current clamp recordings from hippocampal neurons. Further studies of chimeric mutants of rat brain and heart Na+ channels subunits expressed in HEK cells revealed that two amino acid residues of the extracellular loop of D4S3-S4 in rat brain Na+ channel had been related to the binding site for PMTX. PMTXs would serve as a novel, powerful tool for characterization and classification of Na+ channels.

Keywords: pompilidotoxin, neurotoxin, sodium channel inactivation, solitary wasp venom

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