Complexins are small α-helical proteins that modulate neurotransmitter release 
by binding to SNARE complexes during synaptic vesicle exocytosis. They have been 
found to function as fusion clamps to inhibit spontaneous synaptic vesicle 
fusion in the absence of Ca(2+), while also promoting evoked neurotransmitter 
release following an action potential. Complexins consist of an N-terminal 
domain and an accessory α-helix that regulates the activating and inhibitory 
properties of the protein, respectively, and a central α-helix that binds the 
SNARE complex and is essential for both functions. In addition, complexins 
contain a largely unstructured C-terminal domain whose role in synaptic vesicle 
cycling is poorly defined. Here, we demonstrate that the C-terminus of 
Drosophila complexin (DmCpx) regulates localization to synapses and that 
alternative splicing of the C-terminus can differentially regulate spontaneous 
and evoked neurotransmitter release. Characterization of the single DmCpx gene 
by mRNA analysis revealed expression of two alternatively expressed isoforms, 
DmCpx7A and DmCpx7B, which encode proteins with different C-termini that contain 
or lack a membrane tethering prenylation domain. The predominant isoform, 
DmCpx7A, is further modified by RNA editing within this C-terminal region. 
Functional analysis of the splice isoforms showed that both are similarly 
localized to synaptic boutons at larval neuromuscular junctions, but have 
differential effects on the regulation of evoked and spontaneous fusion. These 
data indicate that the C-terminus of Drosophila complexin regulates both 
spontaneous and evoked release through separate mechanisms and that alternative 
splicing generates isoforms with distinct effects on the two major modes of 
synaptic vesicle fusion at synapses.