Vesicle exocytosis stimulated by α‐latrotoxin is mediated by latrophilin and requires both external and stored $ Ca^{2+} $

Abstract α‐Latrotoxin (LTX) stimulates massive neurotransmitter release by two mechanisms: $ Ca^{2+} $‐dependent and ‐independent. Our studies on norepinephrine secretion from nerve terminals now reveal the different molecular basis of these two actions. The $ Ca^{2+} $‐dependent LTX‐evoked vesicle...
Ausführliche Beschreibung

Abstract α‐Latrotoxin (LTX) stimulates massive neurotransmitter release by two mechanisms: $ Ca^{2+} $‐dependent and ‐independent. Our studies on norepinephrine secretion from nerve terminals now reveal the different molecular basis of these two actions. The $ Ca^{2+} $‐dependent LTX‐evoked vesicle exocytosis (abolished by botulinum neurotoxins) is 10‐fold more sensitive to external $ Ca^{2+} $ than secretion triggered by depolarization or A23187; it does not, however, depend on the cation entry into terminals but requires intracellular $ Ca^{2+} $ and is blocked by drugs depleting $ Ca^{2+} $ stores and by inhibitors of phospholipase C (PLC). These data, together with binding studies, prove that latrophilin, which is linked to G proteins and inositol polyphosphate production, is the major functional LTX receptor. The $ Ca^{2+} $‐independent LTX‐stimulated release is not inhibited by botulinum neurotoxins or drugs interfering with $ Ca^{2+} $ metabolism and occurs via pores in the presynaptic membrane, large enough to allow efflux of neurotransmitters and other small molecules from the cytoplasm. Our results unite previously contradictory data about the toxin's effects and suggest that LTX‐stimulated exocytosis depends upon the co‐operative action of external and intracellular $ Ca^{2+} $ involving G proteins and PLC, whereas the $ Ca^{2+} $‐independent release is largely non‐vesicular. Ausführliche Beschreibung