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

Abstract

Proalgesic sensitization of peripheral nociceptors in painful syn-dromes is a complex molecular process poorly understood thatinvolves mobilization of thermosensory receptors to the neuronalsurface. However, whether recruitment of vesicular thermoTRPchannels is a general mechanism underlying sensitization of allnociceptor types or is subtype-specific remains controversial. Wereport that sensitization-induced Ca2+-dependent exocytotic inser-tion of transient receptor potential vanilloid 1 (TRPV1) receptors tothe neuronal plasma membrane is a mechanism specifically usedby 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 responseto a sensitizing insult. Deletion or silencing of calcitonin-gene–related peptide alpha (αCGRP) gene expression drastically reducedproalgesic TRPV1 potentiation in peptidergic nociceptors by abro-gating its Ca2+-dependent exocytotic recruitment. These findingsuncover a context-dependent molecular mechanism of TRPV1 alge-sic sensitization and a previously unrecognized role of αCGRP inLDCV mobilization in peptidergic nociceptors. Furthermore, theseresults imply that concurrent secretion of neuropeptides and chan-nels in peptidergic C-type nociceptors facilitates a rapid modula-tion of pain signaling