alpha-Latrotoxin and its receptors.
alpha-Latrotoxin (alpha-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, alpha-LTX induces massive secretion both in the presence of extracellular Ca(2+) (Ca(2+) (e)) and in its absence; in endocrine cells, it usually requires Ca(2+) (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 alpha-LTX effects is its ability to form cation-permeable channels in artificial lipid bilayers. The mechanism of alpha-LTX pore formation, revealed by cryo-electron microscopy, involves toxin assembly into homotetrameric complexes which harbor a central channel and can insert into lipid membranes. However, in biological membranes, alpha-LTX cannot exert its actions without binding to specific receptors of the plasma membrane. Three proteins with distinct structures have been found to bind alpha-LTX: neurexin Ialpha, latrophilin 1, and receptor-like protein tyrosine phosphatase sigma. Upon binding a receptor, alpha-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, alpha-LTX mutants have been used.
Division of Cell and Molecular Biology, Imperial College London, London, SW7 2AY, UK. y.ushkaryov@imperial.ac.uk
Yuri A
YA
Ushkaryov
Alexis
A
Rohou
Shuzo
S
Sugita
D000818:Animals; D002118:Calcium / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D018377:Neurotransmitter Agents / Q000378:metabolism*; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000037:antagonists & inhibitors; D011955:Receptors, Drug / Q000187:drug effects*; D018000:Receptors, Peptide / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013111:Spider Venoms / Q000737:chemistry / Q000494:pharmacology*
D018377:Neurotransmitter Agents; D011955:Receptors, Drug; D018000:Receptors, Peptide; D011994:Recombinant Proteins; D013111:Spider Venoms; C034800:alpha-latrotoxin receptor; C020763:alpha-latrotoxin; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D002118:Calcium