A Doc uses calcium

Cell 147, 666–677 (2011)

Credit: CELL PRESS

Evoked neurotransmitter release consists of two Ca²⁺-regulated phases: a fast synchronous phase essential for rapid communication with downstream neurons and a slow asynchronous phase that has been implicated in neural network activity. Synaptotagmin 1 (syt1) is the Ca²⁺ sensor of the fast phase, but the sensor of the second phase was unknown. To identify this component, Yao et al. focused on the Doc2 family of cytosolic proteins, which interact with membrane phospholipids in presynaptic terminals in response to Ca²⁺. The authors found that Doc2 isoforms α and β have several features of a Ca²⁺ sensor: binding to and functional dependence on SNARE fusion proteins, binding to membranes in a Ca²⁺-dependent fashion, regulating Ca²⁺-triggered membrane fusion in vitro and dependence on the lipid phosphatidylserine. Compared to syt1, Doc2α and Doc2β bind to membranes with slower kinetics and disassemble from the membrane with much longer timescales. Knockdown of Doc2α or mutation of its Ca²⁺ binding sites also support a role for Doc2α in asynchronous release in cultured neurons. Finally, the authors showed that Doc2 has a role in the induction and maintenance of persistent reverberatory activity in neural networks, in which asynchronous release is known to be important. These results suggest that Doc2 is a Ca²⁺ sensor kinetically tuned to regulate the slow component of transmitter release.