Endoplasmic reticulum membrane contact sites coordinate exocytic site assembly and activity in neuroendocrine cells

2026 · doi:10.64898/2026.02.04.703764
preprint OA: closed
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The paper investigated how endoplasmic reticulum (ER) membrane contact sites contribute to calcium-regulated exocytosis by studying primary bovine chromaffin cells, using electron microscopy of plasma membrane sheets with immunogold labeling. It identified three types of ER contacts involving docked secretory granules—ER–plasma membrane, ER–granule, and tripartite ER–plasma membrane–granule contacts—and found these MCS enriched at exocytic sites containing Orai1 and STIM1. Perturbing the Orai/STIM pathway via constitutive STIM activation or pharmacological Orai1 inhibition reduced the number of exocytotic events, slowed catecholamine release, and disrupted actin organization at granule docking sites. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract Membrane contact sites (MCS) between intracellular organelles regulate lipid exchange, organelles dynamics and spatial organization of signaling pathways, yet their contribution to regulated exocytosis remains poorly understood. Here, we investigated the role of endoplasmic reticulum (ER) MCS in calcium-regulated exocytosis using primary bovine chromaffin cells. Combining electron microscopy on plasma membrane (PM) sheets with immunogold labeling, we identified ER structures contacting docked secretory granules and classified three types of MCS: ER-PM, ER–granule and tripartite ER–PM–granule contacts. These contacts are enriched at exocytic sites and contain Orai1 and STIM1, both known for mediating store-operated calcium release. Functional perturbation of the Orai/STIM pathway revealed that constitutive STIM activation or pharmacological inhibition of Orai1 reduced the number of exocytotic events, slowed catecholamine release and disrupted actin organization at granule docking sites. Together, our findings revealed a previously unrecognized role for ER MCS in organizing exocytic sites and controlling secretion efficiency in neuroendocrine cells. Competing Interest Statement The authors have declared no competing interest. Abbreviations - BTP2 - 3,5-BisTrifluoromethyl Pyrazole - Ca2+ - Calcium Ion - DBH - Dopamine Beta-Hydroxylase - ER - Endoplasmic Reticulum - E-Syts - Extended Synaptotagmins - MCS - Membrane Contact Sites - Orai1 - Calcium Release-Activated Calcium Modulator 1 - PA - Phosphatidic Acid - PIP2 - PhosphatidylInositol-4,5 –bisPhosphate - PLA - Proximity Ligation Assay - PM - Plasma Membrane - PS - Phosphatidyl Serine - SERCA - SarcoEndoplasmic Reticulum Ca2+-ATPase - SG - Secretory Granule - SNAP25 - SyNaptosomal Associated Protein of 25 kDa - STIM1 - STromal Interaction Molecule 1 - TEM - Transmission Electron Microcopy - VAMP - Vesicular Associated Membrane Protein - VAP - VAMP-Associated Proteins

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