VAP organizes presynaptic Ca2+ signaling and synaptic vesicle mobilization through Kv2 membrane contact sites
- 1Division of Arts and Sciences, Department of Biological Sciences, Dartmouth College, Hanover, NH 03755
Abstract
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 Ca2+ 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 Ca2+ exchange and mobilizing synaptic vesicles. We show that the loss of VAP impairs Ca2+ 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 Ca2+ 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 Ca2+ signaling and the synaptic vesicle cycle.
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BibTeX
@article{paton2026organizes,
title = {{VAP organizes presynaptic Ca2+ signaling and synaptic vesicle mobilization through Kv2 membrane contact sites}},
author = {Cameron D. Paton and In Ha Cho and Michael B. Hoppa},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2602106123},
url = {https://doi.org/10.1073/pnas.2602106123},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - VAP organizes presynaptic Ca2+ signaling and synaptic vesicle mobilization through Kv2 membrane contact sites
AU - Cameron D. Paton
AU - In Ha Cho
AU - Michael B. Hoppa
PY - 2026
DA - 2026/10/27
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2602106123
UR - https://doi.org/10.1073/pnas.2602106123
AB - 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 Ca2+ 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 Ca2+ exchange and mobilizing synaptic vesicles. We show that the loss of VAP impairs Ca2+ 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 Ca2+ 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 Ca2+ signaling and the synaptic vesicle cycle.
SN - 0027-8424
SN - 1091-6490
ER -