Alpha-Latrotoxin - Toxicodynamics

Toxicodynamics

α-LTX in its tetrameric form interacts with receptors (neurexins and latrophilins) on the neuronal membrane, which causes insertion of α-LTX into the membrane.

Once the tetramer is inserted into the cell membrane, two mechanism of actions can occur. First insertion may lead to pore formation and possibly other effects and secondly the receptor may be activated which leads to intracellular signaling. The four heads of the tetramer form a bowl surrounding the pore, which is restricted at one point to 10 Å. Millimolar concentrations of Ca2+ and Mg2+ strongly catalyses tetramer formation, suggesting that the tetrametric state is divalent cation-dependent. while EDTA favours formation of the dimer. Research also shows that concentrations of La3+ higher than 100 µM also block tetramerisation. Pore formation can occur in pure lipid membranes, but reconstituted receptors greatly increase pore formation. Biological membranes block pore formation when no α-LTX receptors are present (neurexin, latrophilin, PTPσ). It is also known that the three highly conserved cysteine residues are involved with α-LTX receptor binding, because mutants containing serine instead of cysteine residues did not induce toxicity. The N-terminal domain needs to fold properly, in which the disulfide bonds need to be functional. The α-LTX toxin is bound by a small protein, LMWP or latrodectin. It has been observed that pore formation in lipid bilayers is impossible when latrodectin is unavailable. Lactrodectin has no effect on α-LTX toxicity.