1.C.63 The α-Latrotoxin (Latrotoxin) Family
The α-latrotoxin (αLTX) is a neurotoxin with 21 ANK repeats (residues 490-1199) from the venom of the black widow spider. It forms tetrameric cation selective pores in black lipid membranes with a subunit molecular weight of about 120 kDa. It binds to three distinct receptors in presynaptic plasma membranes of nerve terminals, activating synaptic vesicle exocytosis, probably due to Ca2+ influx and ATP depletion. The receptors are (1) a protein tyrosyl kinase, (2) a 1 TMS cell adhesion protein, and (3) a G-protein coupled receptor (Krasnoperov et al., 2002a,b). It is possible but not established that channel formation alone elicits the biological response. The α-latrotoxin precursor is 1401 aas long and has an N-terminal signal sequence. It may be processed both at its N- and C-termini. It shows extensive regions of sequence similarity to members of the Trp-CC family (TC #1.A.4) (25% identity between residues 628-1159 of Latrotoxin and residues 65-602 in ANKTM1 of Mus musculus (TC #1.A.4.6.1).
Binding of the N terminus of alpha-LTX to one of its specific receptors may either trigger intracellular signaling cascades, resulting in phospholipase C-mediated mobilization of presynaptic Ca2 stores, or lead to the formation of tetrameric pore complexes, allowing extracellular Ca2+ to enter the presynaptic terminal. Alpha-LTX-triggered exocytosis and fulminant transmitter release at autonomic synapses may then provoke a clinical syndrome referred to as ''latrodectism'', characterized by local and incapacitating pain, diaphoresis, muscle fasciculation, tremors and anxiety (Luch 2010). It affects the mitochondrial membrane potential and the proton gradient across synaptic vesicles of nerve terminals (Tarasenko et al. 2008).