Molecular Mechanisms of Synaptic Vesicle Exocytosis and Endocytosis: TRPM7 and Sphingosine-1-phosphate

Synaptic transmission is mediated by synaptic vesicle exocytosis and maintained by subsequent synaptic vesicle endocytosis, the functional integrity of synaptic vesicle exocytosis and endocytosis is thus critical to maintain normal neuronal functions. Notably, the importance of Ca2+ in synaptic vesicle exocytosis and endocytosis has been highlighted by decades of research with many detailed mechanisms still remaining to be elucidated. By applying patch clamp in chromaffin cells and calcium imaging in cortical neuron cultures, we identified that transient receptor potential melastatin 7 (TRPM7), a Ca2+-permeable nonselective cation channel, may function as a Ca2+ influx pathway for endocytosis. In addition, sphingosine-1-phosphate (S1P) is a bioactive signaling lipid and its synthesis by SphK1 may modulate the channel function of TRPM7. By applying amperometry in chromaffin cells and live-cell imaging using pHluorin and synGCaMP6f in cortical neuron cultures, we discovered that S1P / SphK1 pathway is critical for presynaptic Ca2+ levels upon neuronal firing. Besides, our data also illustrated novel regulatory mechanisms of S1P in synaptic vesicle exocytosis: extracellular S1P regulates the rate of exocytosis by activating its membrane receptors and modulating properties of the readily releasable pool, while intracellular S1P controls the fusion pore kinetics.