Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 51, Pages 18345-18350Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1420252111
Keywords
pain transduction; nociception; ion channel; inflammation; sensory neuron
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Funding
- Ministerio de Economia y Competitividad [BFU2012-39092-C02-01, CONSOLIDER-INGENIO 2010 CSD2008-00005]
- Generalitat Valenciana [PROMETEO/2014/011]
- Santiago Grisolia Fellowship from GVA
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Proalgesic sensitization of peripheral nociceptors in painful syndromes is a complex molecular process poorly understood that involves mobilization of thermosensory receptors to the neuronal surface. However, whether recruitment of vesicular thermoTRP channels is a general mechanism underlying sensitization of all nociceptor types or is subtype-specific remains controversial. We report that sensitization-induced Ca2+-dependent exocytotic insertion of transient receptor potential vanilloid 1 (TRPV1) receptors to the neuronal plasma membrane is a mechanism specifically used by peptidergic nociceptors to potentiate their excitability. Notably, we found that TRPV1 is present in large dense-core vesicles (LDCVs) that were mobilized to the neuronal surface in response to a sensitizing insult. Deletion or silencing of calcitonin-generelated peptide alpha (alpha CGRP) gene expression drastically reduced proalgesic TRPV1 potentiation in peptidergic nociceptors by abrogating its Ca2+-dependent exocytotic recruitment. These findings uncover a context-dependent molecular mechanism of TRPV1 algesic sensitization and a previously unrecognized role of aCGRP in LDCV mobilization in peptidergic nociceptors. Furthermore, these results imply that concurrent secretion of neuropeptides and channels in peptidergic C-type nociceptors facilitates a rapid modulation of pain signaling.
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