VAP organizes presynaptic Ca 2+ signaling and synaptic vesicle mobilization through Kv2 membrane contact sites

In neurons, the endoplasmic reticulum (ER) forms an extensive network that establishes membrane contact sites (MCSs) with various organelles including the plasma membrane (PM). While MCSs are known to regulate lipid exchange and Ca 2+ signaling, their specific roles in synaptic transmission remain poorly understood. Here, we demonstrate that the ER-resident proteins VAPA and VAPB are essential for organizing presynaptic Ca 2+ exchange and mobilizing synaptic vesicles. We show that the loss of VAP impairs Ca 2+ loading into both the ER and mitochondria during electrical activity. This regulation occurs primarily through VAP interactions with voltage-gated potassium (Kv2) channels at the PM. Our data suggest that the Kv2–VAP complex organizes presynaptic Ca 2+ signaling outside the active zone. Without this scaffold, vesicle mobilization for exocytosis is strongly impaired and a larger fraction remains trapped in the reserve pool. These findings reveal a role for Kv2–VAP MCSs in coordinating organelle Ca 2+ signaling and the synaptic vesicle cycle.