title: αCGRP is essential for algesic exocytotic mobilization of TRPV1 channels in peptidergic nociceptors.
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.
authors.affiliation: Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche, Spain;
authors.forename: Isabel
authors.initials: I
authors.lastname: Devesa
authors.affiliation: Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche, Spain;
authors.forename: Clotilde
authors.initials: C
authors.lastname: Ferrándiz-Huertas
authors.affiliation: Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche, Spain;
authors.forename: Sakthikumar
authors.initials: S
authors.lastname: Mathivanan
authors.affiliation: Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche, Spain;
authors.forename: Christoph
authors.initials: C
authors.lastname: Wolf
authors.affiliation: Department Ciencias Médicas, Instituto de Investigación en Discapacidades Neurológicas, Facultad de Medicina, Universidad Castilla-La Mancha, 02006 Albacete, Spain;
authors.forename: Rafael
authors.initials: R
authors.lastname: Luján
authors.affiliation: Collège de France, 75005 Paris, France; Institut Pasteur, Centre National de la Recherche Scientifique, Unité de Recherche Associée, 7506 Paris, France; and aferrer@umh.es changeux@noos.fr.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Changeux
authors.affiliation: 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 aferrer@umh.es changeux@noos.fr.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferrer-Montiel
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000502:physiology*; D005089:Exocytosis / Q000502:physiology*; D020868:Gene Silencing; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D009619:Nociceptors / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013373:Substance P / Q000235:genetics; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D010455:Peptides; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C493922:Trpv1 protein, rat; D013373:Substance P; D000255:Adenosine Triphosphate; D015740:Calcitonin Gene-Related Peptide
keywords: inflammation; ion channel; nociception; pain transduction; sensory neuron