Dendrotoxin

Dendrotoxins are a class of neurotoxins produced by mamba snakes that block potassium channels thereby enhancing the release of neurotransmitter. They have proven extremely useful in the study of channel proteins, since they are extremely potent and selective.

Discovery and Naming
"Dendrotoxin" derives from the Latin name of the snakes from whose venom they were isolated: Dendroaspis angusticeps (eastern green mamba) and Dendroaspis polylepis (black mamba). "Dendrotoxin" was first used by Harvey and Karlsson for a particular venom component from the green mamba. Later, when other components were isolated this original toxin was renamed alpha-dendrotoxin, with the newly characterised species labelled beta-, gamma and delta-dendrotoxins. Earlier Joubert's group had fractionated both green and black mamba venoms and isolated the equivalent toxins, but it was only after "dendrotoxin" was discovered that they were recognised as neurotoxins. They originally called alpha-dendrotoxin "C13S2C3" and delta-dendrotoxin "C13S1C3" in honour of their locations in the chromatographic isolation processes. The black mamba components were first named Toxin I and Toxin K and later dendrotoxin-I and dendrotoxin-K.

Structure
Dendrotoxins are small proteins containing 65 to 70 amino acids. Alpha-dendrotoxin and dendrotoxin-I have practically identical amino acid sequences, while delta-dendrotoxin and dendrotoxin-K are very closely related. They all share a resemblance to Kunitz-type protease inhibitors, such as bovine pancreatic trypsin inhibitor (BPTI), though they do not exhibit measurable anti-protease activity. The sequence similarity has led to the belief that the dendrotoxins have evolved from the protease inhibitors. The 3-dimensional structures of alpha-dendrotoxin and dendrotoxin-I have been determined by X-ray crystallography and NMR. Perhaps unsurprisingly, the 3-D structures of the toxins are very similar to that of BPTI.

Function
Harvey's group originally demonstrated that green mamba venom had a facilitatory effect when applied to a nerve-muscle electrophysiology preparation. Harvey and Karlsson then ascribed this action to the isolated alpha-dendrotoxin. Later, Halliwell and others found that alpha-dendrotoxin blocked voltage-activated potassium channels which leads to increased neurotransmitter release.

Dendrotoxin sites in brain
In nature, the main site of action of the dendrotoxins is likely the neuromuscular junction, helping the snake to immobilise its prey. However, by using radiolabelled alpha-dendrotoxin, Dolly and co-workers were able to show that proteins in mammalian brain bound the toxin with high affinity. Subsequently, Rehm & Lazdunski and Parcej & Dolly were able to isolate the binding proteins and could prove that they were potassium channels.