Synaptic Vesicle Exocytosis

National Institute Of Neurological Disorders And Stroke

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Abstract

The function of the nervous system relies on synaptic transmission. Synaptic transmission is mediated by calcium-triggered vesicle fusion, followed by vesicle endocytosis that recycles vesicles. Although significant progress has been made in understanding these processes, much remains unknown. Our goal is to advance the understanding of these synaptic signaling processes. The progress of the last year is described below. 1. The main function of potassium channels has been attributed to their ion conductance, which sets membrane potential and repolarizes action potentials. We recently reported an unexpected function independent of potassium conductance: by organizing the F-actin cytoskeleton in nerve terminals, the Kv3.3 protein facilitates vesicle mobilization to the readily releasable pool and recovery of synaptic depression during repetitive firing. A channel mutation that causes spinocerebellar ataxia inhibits vesicle mobilization and synaptic transmission during repetitive firing by disrupting the ability of the channel to nucleate F-actin. These results reveal novel functions of potassium channels in vesicle mobilization that is crucial in sustaining synaptic transmission during repetitive firing. Potassium channel mutations that impair these non-conducting functions contribute to generation of neurological disorders. 2. The kiss-and-run form of exocytosis has been proposed to mediate endocytosis. However, which forms of endocytosis are contributed by the kiss-and-run mode of exocytosis remains unclear. Here we addressed this question by reconstituting each individual kiss-and-run events from single cells and compared it with the overall endocytosis from the entire cell. We found that kiss-and-run contributes to all kinetically detectable forms of endocytosis in secretory cells, including ultrafast, fast, slow, bulk, overshoot and compensatory endocytosis. This finding establishes kiss-and-run form of exocytosis as one of the major mechanisms underlying all detectable forms of endocytosis. 3. The gastrointestinal tract is known as the largest endocrine organ that encounters and integrates various immune stimulations and neuronal responses due to constant environmental challenges. Enterochromaffin (EC) cells, which function as chemosensors on the gut epithelium, are known to translate environmental cues into serotonin (5-HT) production, contributing to intestinal physiology. However, how immune signals participate in gut sensation and neuroendocrine response remains unclear. Interleukin-33 (IL-33) acts as an alarmin cytokine by alerting the system of potential environmental stresses. We here demonstrate that IL-33 induced instantaneous peristaltic movement and facilitated Trichuris muris expulsion. We found that IL-33 could be sensed by EC cells, inducing release of 5-HT. IL-33-mediated 5-HT release activated enteric neurons, subsequently promoting gut motility. Mechanistically, IL-33 triggered calcium influx via a non-canonical signaling pathway specifically in EC cells to induce 5-HT secretion. Our data establish an immune-neuroendocrine axis in calibrating rapid 5-HT release for intestinal homeostasis.