Complexins Regulate a Late Step in Ca 2 1 - Dependent Neurotransmitter Release

Munc13-1 functions as an essential synaptic vesicle priming factor (Brose et al., 2000). Vesicle fusion, on the Abteilung Membranbiophysik Am Faßberg 11 other hand, is thought to be mediated by the concerted action of the synaptic vesicle protein Synaptobrevin/ D-37077 Gö ttingen Bundesrepublik Deutschland VAMP (vesicle associated membrane protein) and the two synaptic plasma membrane proteins Syntaxin and SNAP25 (synaptosomal associated protein of 25 kDa). These proteins form a thermodynamically stable ternary Department of Molecular Genetics and Howard Hughes Medical Institute complex, the core complex, whose association is thought to represent the primed state of a vesicle and/ 6000 Harry Hines Boulevard Dallas, Texas 75235 or to mediate vesicle fusion (Calakos and Scheller, 1999; Jahn and Sü dhof, 1999). Munc13-1 may mediate its priming effect by modulating Syntaxin function, thereby promoting core complex formation at the active zone (Brose et al., 2000). The best candidates for the exocy-Summary totic Ca 2ϩ sensor are the synaptic vesicle protein Synap-totagmin I and related proteins (Geppert and Sü dhof, Synaptic vesicle fusion at synapses is triggered by 1998). increases in cytosolic Ca 2؉ levels. However, the iden-In a search for proteins that act downstream of tity of the Ca 2؉ sensor and the transduction mecha-Munc13-1-mediated synaptic vesicle priming, we found nism of the Ca 2؉ trigger are unknown. We show that recently that levels of Complexin I (CPX I) were signifi-Complexins, stoichiometric components of the exocy-cantly reduced in Munc13-1 deletion mutants. This indi-totic core complex, are important regulators of trans-cated an altered half-life of this protein in the Munc13-1 mitter release at a step immediately preceding vesicle mutant background (Augustin et al., 1999b), suggesting fusion. Neurons lacking Complexins show a dramati-that CPX I may act downstream of Munc13-1-mediated cally reduced transmitter release efficiency due to de-vesicle priming, e.g., in Ca 2ϩ triggered fusion. creased Ca 2؉ sensitivity of the synaptic secretion pro-In mammals, CPXs form a family of two closely related cess. Analyses of mutant neurons demonstrate that proteins (CPX I and II) that were initially identified as Complexins are acting at or following the Ca 2؉-trig-stoichiometric components of the core complex (Ishi-gering step of fast synchronous transmitter release zuka et al., 1995; McMahon et al., 1995; Takahashi et by regulating the exocytotic Ca 2؉ sensor, its interac-al., 1995). There is no evidence for additional CPX iso-tion with the core complex fusion machinery, or the forms in current human genome databases. CPXs are …