Synergistic control of neurotransmitter release by different members of the synaptotagmin family

Quantal neurotransmitter release at nerve terminals is tightly regulated by the presynaptic Ca²⁺ concentration. Here, we summarise current advances in understanding how the interplay between presynaptic Ca²⁺ dynamics and different Ca²⁺ release sensors shapes action potential-evoked release on a timescale from hundreds of microseconds to hundreds of milliseconds. In particular, we review recent studies that reveal the synergistic roles of the low Ca²⁺ affinity/fast release sensors synaptotagmins 1, 2 and 9 and the high affinity/slow release sensor synaptotagmin 7 in the regulation of synchronous and asynchronous release and of short-term synaptic plasticity. We also examine new biochemical and structural data and outline a working model that could potentially explain the cooperative roles of different synaptotagmins in molecular terms.