Tuning the Size of Large Dense‐Core Vesicles and Quantal Neurotransmitter Release via Secretogranin II Liquid–Liquid Phase Separation

Large dense‐core vesicles (LDCVs) are larger in volume than synaptic vesicles, and are filled with multiple neuropeptides, hormones, and neurotransmitters that participate in various physiological processes. However, little is known about the mechanism determining the size of LDCVs. Here, it is reported that secretogranin II (SgII), a vesicle matrix protein, contributes to LDCV size regulation through its liquid–liquid phase separation in neuroendocrine cells. First, SgII undergoes pH‐dependent polymerization and the polymerized SgII forms phase droplets with Ca2+ in vitro and in vivo. Further, the Ca2+‐induced SgII droplets recruit reconstituted bio‐lipids, mimicking the LDCVs biogenesis. In addition, SgII knockdown leads to significant decrease of the quantal neurotransmitter release by affecting LDCV size, which is differently rescued by SgII truncations with different degrees of phase separation. In conclusion, it is shown that SgII is a unique intravesicular matrix protein undergoing liquid–liquid phase separation, and present novel insights into how SgII determines LDCV size and the quantal neurotransmitter release. The mystery of what fundamentally determines the size of large dense‐core vesicles (LDCVs) in neuroendocrine cells is uncovered. Secretogranin II, an intravesicular matrix protein, undergoes liquid–liquid phase separation in vitro and in vivo to determine the size/volume of LDCVs, thus tuning the quantal neurotransmitters release.