<h3>Title</h3>
<h3>Can a neurotransmitter control its own exocytosis?</h3>
<p><strong><span style="text-decoration: underline;">Abstract</span> :</strong></p>
<p style="text-align: justify;">It has been observed that vesicular exocytosis of neurotransmitters results in “quantal release”, i.e., each vesicle releases a similar amount of neurotransmitter. However, vesicular neurotransmitter uptake by the transporters is not an instantaneous process; therefore, there would always be vesicles with different concentrations of neurotransmitters. How does the cell know which vesicle contains an adequate amount of neurotransmitters, and is therefore “mature” enough to be exocytosed? This problem is even more relevant for somatic neurotransmitter vesicles (such as serotonergic ones), where there is a rather large variation of the “age” of vesicles after their formation. We propose that serotonin interacts with the vesicular membranes, resulting in a change in the membrane mechanical properties, which in turn provides a signal for exocytosis. We have recently shown that serotonin incorporation reduces the mechanical stiffness of artificial lipid bilayers (1). Here we show that for serotonergic vesicles in a neuronal cell line, the vesicular membrane becomes less ordered as the vesicular serotonin concentration increases from a few mM to a few hundred mM. Using three-photon microscopy, we quantify vesicular serotonin concentration in a label-free manner.  We simultaneously perform spectral imaging of the dye Nile red to measure vesicular membrane order. We find a negative correlation between the serotonin intensity and membrane order. Fluorescence lifetime imaging of the mechanosensitive dye FliptR corroborate these results, proving that change of membrane order provides a readout of the intra-vesicular serotonin concentration. Additionally, upon depolarization of the cells, we observe preferential exocytosis of vesicles with lower membrane order.  We infer that membrane mechanics provides a functional readout of the lumenal serotonin concentration, enabling the exocytosis process to preferentially release the well-filled vesicles.</p>
<p>(1) Dey et al., Chem. Eur. J., Volume27 (2021) 7533-7541</p>