α-Latrotoxin and Its Receptors

α-Latrotoxin (α-LTX) from black widow spider venom induces exhaustive release of neurotransmitters from vertebrate nerve terminals and endocrine cells. This 130-kDa protein has been employed for many years as a molecular tool to study exocytosis. However, its action is complex: in neurons, α-LTX induces massive secretion both in the presence of extracellular Ca2+ (Ca2+e) and in its absence; in endocrine cells, it usually requires Ca2+e. To use this toxin for further dissection of secretory mechanisms, one needs an in-depth understanding of its functions. One such function that explains some α-LTX effects is its ability to form cation-permeable channels in artificial lipid bilayers. The mechanism of α-LTX pore formation, revealed by cryo-electron microscopy, involves toxin assembly into homotetrameric complexes which harbour a central channel and can insert into lipid membranes. However, in biological membranes, α-LTX cannot exert its actions without binding to specific receptors of the plasma membrane. Three proteins with distinct structures have been found to bind α-LTX: neurexin Iα, latrophilin 1 and receptor-like protein tyrosine phosphatase σ. Upon binding a receptor, α-LTX forms channels permeable to cations and small molecules; the toxin may also activate the receptor. To distinguish between the pore- and receptor-mediated effects, and to study structure-function relationships in the toxin, α-LTX mutants have been used. At least one non-pore-forming α-LTX mutant can activate latrophilin, a G protein-coupled receptor, causing release of Ca2+ from intracellular stores. Latrophilin action still requires Ca2+e and may trigger transmitter secretion either by itself or by activating Ca2+-channels and/or inducing Ca2+ waves. These results reveal two Ca2+e-dependent mechanisms of α-LTX action (membrane pore formation and signalling via latrophilin), but how α-LTX triggers Ca2+e-independent neurotransmitter release still remains unexplained. Hypotheses for this action include direct interaction with intracellular components involved in exocytosis or the effects of α-LTX pores.