Referenced in: none

Automatically associated channels: TRP , TRPV , TRPV1

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

Authors: Isabel Devesa, Clotilde Ferrándiz-Huertas, Sakthikumar Mathivanan, Christoph Wolf, Rafael Lujan, Jean-Pierre Changeux, Antonio Ferrer-Montiel

Journal, date & volume: Proc. Natl. Acad. Sci. U.S.A., 2014 Dec 23 , 111, 18345-50

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25489075

Abstract
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.