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α-Latrotoxin (LTX) stimulates vesicular exocytosis by at least two mechanisms that include (1) receptor binding-stimulation and (2) membrane pore formation. Here, we use the toxin mutant LTX N4C to selectively study the receptor-mediated actions of LTX. LTX N4C binds to both LTX receptors (latrophilin and neurexin) and greatly enhances the frequency of spontaneous and miniature EPSCs recorded from CA3 pyramidal neurons in hippocampal slice cultures. The effect of LTX N4C is reversible and is not attenuated by La 3+ that is known to block LTX pores. On the other hand, LTX N4C action, which requires extracellular Ca 2+ , is inhibited by thapsigargin, a drug depleting intracellular Ca 2+ stores, by 2-aminoethoxydiphenyl borate, a blocker of inositol(1,4,5)-trisphosphate-induced Ca 2+ release, and by U73122, a phospholipase C inhibitor. Furthermore, measurements using a fluorescent Ca 2+ indicator directly demonstrate that LTX N4C increases presynaptic, but not dendritic, free Ca 2+ concentration; this Ca 2+ rise is blocked by thapsigargin, suggesting, together with electrophysiological data, that the receptor-mediated action of LTX N4C involves mobilization of Ca 2+ from intracellular stores. Finally, in contrast to wild-type LTX, which inhibits evoked synaptic transmission probably attributable to pore formation, LTX N4C actually potentiates synaptic currents elicited by electrical stimulation of afferent fibers. We suggest that the mutant LTX N4C , lacking the ionophore-like activity of wild-type LTX, activates a presynaptic receptor and stimulates Ca 2+ release from intracellular stores, leading to the enhancement of synaptic vesicle exocytosis.


Journal article


Journal of Neuroscience

Publication Date





4044 - 4053