Complexin facilitates exocytosis and synchronizes vesicle release in two secretory model systems

Key points center dot Knockout (KO) of complexin in mouse neuromuscular junctions (NMJs) and adrenal chromaffin cells causes a reduction and a loss in synchronicity in calcium-mediated exocytosis. center dot A train of high-frequency stimuli induces synaptic facilitation rather than depression in Complexin 1 KO NMJs, and the degree of facilitation is sensitive to calcium buffering. center dot There is a specific reduction of the vesicle pool close to the calcium channels in Complexin 2 KO chromaffin cells, which can be rescued by heterologous expression of either Complexin 1 or Complexin 2. center dot Complexin synchronizes vesicle release through facilitating vesicle and calcium channel coupling. Abstract Complexins (Cplxs) are small, SNARE-associated proteins believed to regulate fast, calcium-triggered exocytosis. However, studies have pointed to either an inhibitory and/or facilitatory role in exocytosis, and the role of Cplxs in synchronizing exocytosis is relatively unexplored. Here, we compare the function of two types of complexin, Cplx 1 and 2, in two model systems of calcium-dependent exocytosis. In mouse neuromuscular junctions (NMJs), we find that lack of Cplx 1 significantly reduces and desynchronizes calcium-triggered synaptic transmission; furthermore, high-frequency stimulation elicits synaptic facilitation, instead of normal synaptic depression, and the degree of facilitation is highly sensitive to the amount of cytoplasmic calcium buffering. In Cplx 2-null adrenal chromaffin cells, we also find decreased and desynchronized evoked release, and identify a significant reduction in the vesicle pool close to the calcium channels (immediately releasable pool, IRP). Viral transduction with either Cplx 1 or 2 rescues both the size of the evoked response and the synchronicity of release, and it restores the IRP size. Our findings in two model systems are mutually compatible and indicate a role of Cplx 1 and 2 in facilitating vesicle priming, and also lead to the new hypothesis that Cplxs may synchronize vesicle release by promoting coupling between secretory vesicles and calcium channels.