biostudies-literatureLin ZPeking UniversityChina Postdoctoral Science FoundationNational Natural Science Foundation of ChinaNational Postdoctoral Program for Innovative TalentsNational Key Research and Development Program of Chinae2202263https://www.ebi.ac.uk/biostudies/studies/S-EPMC9507364biostudies-literatureUnknown9(27)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.Advanced science (Weinheim, Baden-Wurttemberg, Germany)Tuning the Size of Large Dense-Core Vesicles and Quantal Neurotransmitter Release via Secretogranin II Liquid-Liquid Phase Separation.PMC950736431930061321712333132790131171026BX201900122020M670029316708433133002431821091217903902016YFA0500401317611330168200075721790394Li JWang CZhu FDu XLin ZHang YQiao ZZhang QZhou ZLi YZhang ZJiang XLiu BYin LfalseTuning 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.2022-01-01T00:00:00Z2022 Sep2026-05-31T02:13:06.054Z2025-02-19T01:22:03.132ZS-EPMC95073643589689610.1002/advs.202202263