Liquid-liquid phase separation within dense-core vesicles in sympathetic adrenal chromaffin cells

The neural communication process heavily relies on vesicular release of neurotransmitters and/or neuromodulators primarily from synaptic vesicles (SVs) or dense-core vesicles (DCVs), within neurons and neuroendocrine cells. SVs (∼40 nm) are responsible for releasing classical neurotransmitters, while DCVs (100-500 nm in diameter) release both classic neurotransmitters and neuropeptides. DCVs contain a variety of neuropeptides, hormones, and neurotransmitters, playing crucial roles in diverse physiological processes, such as brain development, neurogenesis, and synaptic plasticity. However, the biogenesis of DCVs and the sorting mechanism of different neuropeptides into DCVs remained largely unknown. Recent studies have revealed that liquid-liquid phase separation (LLPS) of matrix protein-chromogranins plays pivotal roles in the formation of DCVs and the sorting process of neurotransmitters/neuromodulators in endocrine cells. Here we highlight recent advancements in mechanisms of LLPS’s regulation of DCVs [1, 2] , which selectively affect release of some co-transmitters (catecholamines) but not others (i.e. ATP) [3] . We term this phenomenon “1-2-2”: 1 vesicle, 2 transmitters (catecholamine and ATP), 2 release modes (quanta and sub-quanta).