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

Loss of VAPA/VAPB disrupts presynaptic Ca2+ exchange and synaptic vesicle mobilization, with Kv2 channel–dependent ER contact sites organizing Ca2+ signaling outside the active zone.

• Why it matters: Membrane contact sites are known to regulate lipid exchange and Ca2+ signaling, but their specific roles in synaptic transmission and vesicle cycling remain unclear.
• What they did: Neurons were analyzed for ER Ca2+ loading into the ER and mitochondria during electrical activity after VAP loss, focusing on VAP interactions with voltage-gated potassium (Kv2) channels at the plasma membrane.
• The result: Without the Kv2–VAP scaffold, vesicle mobilization for exocytosis is strongly impaired and a larger fraction remains trapped in the reserve pool, linking Kv2–VAP MCSs to coordinated organelle Ca2+ signaling and the synaptic vesicle cycle.