Synaptotagmins I and IV promote transmitter release independently of Ca2+ binding in the C2A domain (original) (raw)

At nerve terminals, a focal and transient increase in intracellular Ca 21 triggers the fusion of neurotransmitter-filled vesicles with the plasma membrane. The most extensively studied candidate for the Ca 21 -sensing trigger is synaptotagmin I, whose Ca 21dependent interactions with acidic phospholipids and syntaxin 1 have largely been ascribed to its C 2 A domain 2-6 , although the C 2 B domain also binds Ca 21 (refs 7, 8). Genetic tests of synaptotagmin I have been equivocal as to whether it is the Ca 21 -sensing trigger of fusion . Synaptotagmin IV, a related isoform that does not bind Ca 21 in the C 2 A domain, might be an inhibitor of release . We mutated an essential aspartate of the Ca 21 -binding site of the synaptotagmin I C 2 A domain and expressed it in Drosophila lacking synaptotagmin I. Here we show that, despite the disruption of the binding site, the Ca 21 -dependent properties of transmission were not altered. Similarly, we found that synaptotagmin IV could substitute for synaptotagmin I. We conclude that the C 2 A domain of synaptotagmin is not required for Ca 21 -dependent synaptic transmission, and that synaptotagmin IV promotes rather than inhibits transmission.

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