New insight in spontaneous neurotransmitter release

01 March 2010

The CNCR team of Sander Groffen and Matthijs Verhage discovered that the Doc2b gene is a Ca2+-sensor responsible for triggering spontaneous release events. Their findings are published as a full length article in the accelerated online version of Science on Febr 11th, 2010.

Fusion of synaptic vesicles in the synapses of the brain occurs in three different phases, either tightly coupled to action potentials (synchronous release), immediately following action potentials (asynchronous release) or as stochastic events in the absence of action potentials (spontaneous release). The Ca2+-sensors for synchronous release have been identified about a decade ago (synaptotagmin genes). While spontaneous release events were first identified more than 50 years ago, the mechanism that induces their release has remained elusive.

CNCR researchers Sander Groffen and Matthijs Verhage together with their collaborators at CNCR and colleagues in Cambridge, UK, have now discovered that Double C2 domain (Doc2) proteins act as Ca2+-sensors to trigger spontaneous release in hippocampal and Purkinje cell synapses.

Although Doc2 proteins are cytosolic, they function analogously to synaptotagmin but with a higher Ca2+-sensitivity and superior in vitro fusion-efficiency. Doc2 proteins bound to the macromolecular protein complexes that drive fusion (SNARE complexes) in competition with synaptotagmins. Thus, different classes of multiple C2 domain-containing molecules trigger synchronous versus spontaneous fusion, which suggests a general mechanism for synaptic vesicle fusion triggered by the combined actions of SNARE proteins and multiple C2 domain-containing proteins.