BPS2026 – Serotonin self-regulates its exocytosis by modulating vesicular membrane properties

The process of exocytosis is a fundamental component of cellular signaling. It involves large deformations and transient rupture of the membrane. While the protein machinery that drives this energy-consuming process has been extensively investigated, it is not known to what extent the physical properties of the membrane affect this process. Some amphiphilic molecules, such as the neurotransmitter serotonin, can induce disorder in artificial lipid bilayers to lower their resistance to deformation and rupture. Here, we probe whether such interactions can change vesicular membrane properties and influence the exocytosis probability of serotonergic vesicles in a living cell. We track individual somatic vesicles with label-free three-photon imaging of serotonin and observe that the serotonin concentration directly correlates with vesicular release probability. Simultaneous spectral and lifetime imaging of membrane-reporter dyes shows that vesicular membrane fluidity increases with serotonin concentration, which increases the docking time of the vesicles at the plasma membrane and facilitates exocytosis. This is an accessory control pathway for exocytosis, revealing that nature uses the membrane as a transducer to effectively couple vesicular loading and exocytosis of serotonergic vesicles. Our findings suggest that small amphiphilic molecules can provide receptor-independent, membrane-mediated regulation of exocytosis. Indeed, we found several other small molecules, such as the physiological molecule N-acetyl serotonin, the psychedelic drug DOI, and the Trk-inhibitor ANA 12 to be effective regulators of exocytosis.