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Implication de la calmoduline et de la V-ATPase dans la fusion membranaire et la libération de neurotransmetteurs

Action potential-evoked neurotransmitter release relies on Ca2+-driven synaptic vesicle fusion with the plasma membrane. Fusion involves assembly of the vesicular protein VAMP2 (a v-SNARE) with the plasma membrane proteins syntaxin 1 and SNAP25 (t-SNAREs) into a tight trans complex at the interface between the bilayers, and is triggered by synaptotagmin, a fusogenic Ca2+-sensor. Additional Ca2+-sensors are likely to participate in release triggering and fusion pore dynamics, and notably our understanding of calmodulins actions in exocytosis remains elusive. By means of a FRET-derived method, we demonstrate that Ca2+/calmodulin inhibits SNARE complex assembly and SNAREdependent membrane fusion in vitro, by binding to the juxtamembrane regions of VAMP2 and syntaxin 1. The newly-identified calmodulin binding site on syntaxin overlaps with the synaptotagmin- interacting region, and the two interactions are mutually exclusive, suggesting antagonistic roles for the two sensors in membrane fusion. Moreover, recent data point to the involvement of the V0 sector of the proton pump V-ATPase in various membrane fusion events. They indicate that pore-forming c-subunits hexamers confer Ca2+- dependent release of acetylcholine to synthetic liposomes in the presence of calmodulin. Using yeasttwo- hybrid and SPR, we have identified a direct link between the c-subunit loop 3-4 and the v-SNARE VAMP2, involving the calmodulin-binding domain of the latter. Disturbing this interaction in vivo by acute injection of an interfering peptide inhibited neurotransmission, suggesting that association of the exocytotic machinery with the putative proteic pore is involved in neurotransmitter release.