Devesa Isabel, Ferrándiz-Huertas Clotilde, Mathivanan Sakthikumar, Wolf Christoph, Luján Rafael, Changeux Jean-Pierre, Ferrer-Montiel Antonio
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;
Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):18345-50. doi: 10.1073/pnas.1420252111. Epub 2014 Dec 8.
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.
疼痛综合征中周围伤害感受器的促痛敏化是一个复杂的分子过程，目前了解甚少，它涉及热感觉受体向神经元表面的移动。然而，囊泡性热TRP通道的募集是所有伤害感受器类型敏化的普遍机制还是亚型特异性的，仍存在争议。我们报告，敏化诱导的瞬时受体电位香草酸受体1（TRPV1）受体依赖于Ca(2+)的胞吐插入到神经元质膜是肽能伤害感受器用来增强其兴奋性的一种特异性机制。值得注意的是，我们发现TRPV1存在于大致密核心囊泡（LDCV）中，这些囊泡在受到敏化刺激时会移动到神经元表面。降钙素基因相关肽α（αCGRP）基因表达的缺失或沉默通过消除其依赖于Ca(2+)的胞吐募集，显著降低了肽能伤害感受器中促痛性TRPV1的增强作用。这些发现揭示了TRPV1痛觉敏化的一种依赖于环境的分子机制，以及αCGRP在肽能伤害感受器LDCV移动中以前未被认识的作用。此外，这些结果表明，肽能C型伤害感受器中神经肽和通道的同时分泌促进了疼痛信号的快速调节。
