[Seminar] Mechanisms of neuronal algesic potentiation: Thermosensory channels and beyond

Seminar

Title: Mechanisms of neuronal algesic potentiation: Thermosensory channels and beyond

Speaker: Antonio Ferrer-Montiel

Affiliation: Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Elche, Spain.

Abstract:

Sensitization of sensory neurons upon tissue or nerve damage induces a drastic increase of their excitability, leading to the sensory hypersensitivity that underlies thermal hyperalgesia and allodynia. A major player in the onset and maintenance of nociceptor sensitization is the Transient Receptor Potential Vanilloid 1 (TRPV1), a thermoTRP receptor expressed by peptidergic and non-peptidergic sensory neurons whose activity is highly potentiated by pro-inflammatory agents. TRPV1 is a polymodal channel that can be activated by noxious heat (>42ºC), acidic pH (pH<5.9), voltage and numerous chemical ligands. TRPV1 is a non-selective cation channel with moderate permeability for divalent cations. TRPV1 is subjected to complex regulation, from gene expression to post-translational modification as well as subcellular compartmentalization and association with regulatory proteins. Cumulative evidence suggests that pro-inflammatory agents may additionally regulate channel activity by increasing the expression and delivery of new channels to the neuronal surface. We have investigated this hypothesis and found that TRPV1 is rapidly inserted, through an SNARE-dependent exocytotic process, into the plasma membrane of nociceptors upon exposure to pro-algesic compounds such as ATP and NGF. Furthermore, analysis of channel sensitization in both nociceptor subpopulations demonstrate that inflammation-dependent insertion of TRPV1 channels in the cell surface is a context-dependent mechanism. Notably, blockers of neuronal regulated exocytosis reduce the pro-algesic neuronal mobilization of TRPV1 and exhibit long lasting in vivo anti-nociceptive activity. Together, these findings demonstrate that recruitment of TRPV1 channels by algogens is a pivotal mechanism underlying nociceptor sensitization under pathological conditions.
Funded by: MINECO, CONSOLIDER-INGENIO 2010 and GVA.

Invited Speaker in ITQB PhD Programs MolBioS