Research ArticleNeuroscience

Ligand- and voltage-gated Ca2+ channels differentially regulate the mode of vesicular neuropeptide release in mammalian sensory neurons

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Sci. Signal.  20 Jun 2017:
Vol. 10, Issue 484, eaal1683
DOI: 10.1126/scisignal.aal1683

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Kiss-and-run or a full commitment?

Communication between sensory neurons underlies our sense of touch and temperature and is mediated by the release of neuropeptides from exocytic vesicles. In response to calcium influx, these vesicles can either fuse completely with the synaptic membrane and release all of their contents (called full-fusion release) or fuse transiently and release only some of their contents (called “kiss-and-run” release). Using single-vesicle imaging in rodent sensory neurons, Wang et al. discovered that the release mode used by a neuron was determined by the type of calcium channel that was activated. Activation of voltage-gated calcium channels (VGCCs) promoted greater calcium influx at the plasma membrane, which inhibited a protein that limits fusion pore size, thus enabling full-fusion release. Activation of ligand-gated TRPV1 calcium channels promoted partial but pulsed and thus more prolonged neuropeptide release. The findings provide insight into how calcium channels influence sensory neurotransmission.

Abstract

Neuropeptides released from dorsal root ganglion (DRG) neurons play essential roles in the neurotransmission of sensory inputs, including those underlying nociception and pathological pain. Neuropeptides are released from intracellular vesicles through two modes: a partial release mode called “kiss-and-run” (KAR) and a full release mode called “full fusion–like” (FFL). Using total internal reflection fluorescence (TIRF) microscopy, we traced the release of pH-sensitive green fluorescent protein–tagged neuropeptide Y (pHluorin-NPY) from individual dense-core vesicles in the soma and axon of single DRG neurons after Ca2+ influx through either voltage-gated Ca2+ channels (VGCCs) or ligand-gated transient receptor potential vanilloid 1 (TRPV1) channels. We found that Ca2+ influx through VGCCs stimulated FFL and a greater single release of neuropeptides. In contrast, Ca2+ influx through TRPV1 channels stimulated KAR and a pulsed but prolonged release of neuropeptides that was partially mediated by Dynamin 1, which limits fusion pore expansion. Suppressing the Ca2+ gradient to an extent similar to that seen after TRPV1 activation abolished the VGCC preference for FFL. The findings suggest that by generating a steeper Ca2+ gradient, VGCCs promote a more robust fusion pore opening that facilitates FFL. Thus, KAR and FFL release modes are differentially regulated by the two principal types of Ca2+-permeable channels in DRG neurons.

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