Chromogranin A-phosphatidic acid association coordinates late stages of regulated exocytosis

Chromogranin A is a major component of secretory granules that contributes to granule biogenesis, cargo organization and regulated secretion in neuroendocrine cells. We previously identified a phosphatidic acid (PA)-binding domain (PABD) within CgA that promotes secretory granule formation by remodeling trans-Golgi network membranes. Here, we investigate whether this lipid-protein association also contributes to the late stages of regulated exocytosis. Using fluorescence lifetime imaging microscopy combined with Förster resonance energy transfer, we find that CgA undergoes a stimulation-dependent association with PA at exocytic sites in living cells. Immunofluorescence and electron microscopy further show that CgA remains transiently associated with fused secretory granule membranes. Functional analyses reveal that disruption of the PABD alters secretory granule exocytosis by accelerating CgA release, modifying quantal catecholamine release and fusion pore dynamics, and changing the early kinetics of secretory granule membrane retrieval. Together, these findings support a model in which the CgA/PA association is not restricted to secretory granule biogenesis but also contributes to the temporal coordination of multiple post-fusion events during regulated secretion. This work identifies a lipid-protein interaction that links distinct stages of the secretory granule life cycle in neuroendocrine cells. Chromogranin A binds phosphatidic acid at exocytic sites, coordinating secretion beyond granule formation. Disrupting this interaction alters cargo release, fusion pore dynamics, and membrane retrieval, linking distinct stages of the secretory granule life cycle.