“Spontaneous” Release Trigger Synaptic vesicle release occurs in different phases that can be tightly coupled to action potentials (synchronous), immediately following action potentials (asynchronous), or as stochastic events not triggered by action potentials (spontaneous). The vesicle protein synaptotagmin is thought to act as the Ca ²⁺ sensor in the synchronous phase, but for the other two phases, Ca ²⁺ sensors have not been identified. Groffen et al. (p. 1614 , published online 11 February) now show that cytoplasmic proteins known as Doc2 (double C2 domain) proteins are required for spontaneous release. Doc2 proteins promote membrane fusion in response to exceptionally low increases in Ca ²⁺ , and are several orders of magnitude more sensitive to Ca ²⁺ than synaptotagmin. Doc2 and synaptotagmin compete for SNARE-complex binding during membrane fusion. A mutation that abolishes the Ca ²⁺ dependence of Doc2b also abolishes the Ca ²⁺ dependence of spontaneous release. Thus, Doc2 is a high-affinity Ca ²⁺ sensor for spontaneous release that competes with synaptotagmin for SNARE complex binding.