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

Abstract

Key points 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. 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. 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. 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.