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Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):18345-50. doi: 10.1073/pnas.1420252111. Epub 2014 Dec 8.

αCGRP is essential for algesic exocytotic mobilization of TRPV1 channels in peptidergic nociceptors.

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Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche, Spain;
Department Ciencias Médicas, Instituto de Investigación en Discapacidades Neurológicas, Facultad de Medicina, Universidad Castilla-La Mancha, 02006 Albacete, Spain;
Collège de France, 75005 Paris, France; Institut Pasteur, Centre National de la Recherche Scientifique, Unité de Recherche Associée, 7506 Paris, France; and
Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche, Spain; Unidad de Biofísica, Universidad del País Vasco/Euskal Herriko Unibertsitatea, Consejo Superior de Investigaciones Científicas, 48940 Leioa, Spain


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 Ca(2+)-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-gene-related peptide alpha (αCGRP) gene expression drastically reduced proalgesic TRPV1 potentiation in peptidergic nociceptors by abrogating its Ca(2+)-dependent exocytotic recruitment. These findings uncover a context-dependent molecular mechanism of TRPV1 algesic sensitization and a previously unrecognized role of αCGRP 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.


inflammation; ion channel; nociception; pain transduction; sensory neuron

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