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The Journal of Neuroscience, May 15, 2003, 23(10):4044-4053

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The -Latrotoxin Mutant LTX^N4C Enhances Spontaneous and Evoked Transmitter Release in CA3 Pyramidal Neurons

Marco Capogna,¹ Kirill E. Volynski,² Nigel J. Emptage,³ and Yuri A. Ushkaryov²

¹Medical Research Council, Anatomical Neuropharmacology Unit, Oxford, OX1 3TH, United Kingdom, ²Department of Biological Sciences, Imperial College, London, SW7 2AY, United Kingdom, and ³Department of Pharmacology, University of Oxford, OX1 3TH, United Kingdom

-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 La³⁺ that is known to block LTX pores. On the other hand, LTX^N4C action, which requires extracellular Ca²⁺, is inhibited by thapsigargin, a drug depleting intracellular Ca²⁺ stores, by 2-aminoethoxydiphenyl borate, a blocker of inositol(1,4,5)-trisphosphate-induced Ca²⁺ release, and by U73122, a phospholipase C inhibitor. Furthermore, measurements using a fluorescent Ca²⁺ indicator directly demonstrate that LTX^N4C increases presynaptic, but not dendritic, free Ca²⁺ concentration; this Ca²⁺ rise is blocked by thapsigargin, suggesting, together with electrophysiological data, that the receptor-mediated action of LTX^N4C involves mobilization of Ca²⁺ 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 Ca²⁺ release from intracellular stores, leading to the enhancement of synaptic vesicle exocytosis.

Key words: -latrotoxin; mutant; hippocampal slice culture; spontaneous synaptic transmission; evoked synaptic transmission; transmitter release; receptor; latrophilin; neurexin; intracellular Ca²⁺ stores

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Received Nov. 13, 2002; revised Mar. 3, 2003; accepted Mar. 4, 2003.

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