title: Regulated exocytosis contributes to protein kinase C potentiation of vanilloid receptor activity.
abstract: The vanilloid receptor-1 (TRPV1) plays a key role in the perception of peripheral thermal and inflammatory pain. TRPV1 expression and channel activity are notably up-regulated by proalgesic agents. The transduction pathways involved in TRPV1 sensitization are still elusive. We have used a yeast two-hybrid screen to identify proteins that associate with the N terminus of TRPV1. We report that two vesicular proteins, Snapin and synaptotagmin IX (Syt IX), strongly interact in vitro and in vivo with the TRPV1 N-terminal domain. In primary dorsal root ganglion neurons, TRPV1 co-distributes in vesicles with Syt IX and the vesicular protein synaptobrevin. Neither Snapin nor Syt IX affected channel function, but they notably inhibited protein kinase C (PKC)-induced potentiation of TRPV1 channel activity with a potency that rivaled the blockade evoked by botulinum neurotoxin A, a potent blocker of neuronal exocytosis. Noteworthily, we found that PKC activation induced a rapid delivery of functional TRPV1 channels to the plasma membrane. Botulinum neurotoxin A blocked the TRPV1 membrane translocation induced by PKC that was activated with a phorbol ester or the metabotropic glutamate receptor mGluR5. Therefore, our results indicate that PKC signaling promotes at least in part the SNARE-dependent exocytosis of TRPV1 to the cell surface. Taken together, these findings imply that activity-dependent delivery of channels to the neuronal surface may contribute to the buildup and maintenance of thermal inflammatory hyperalgesia in peripheral nociceptor terminals.
authors.affiliation: Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Avenida del Ferrocarril s/n, 03202 Elche (Alicante), Spain.
authors.forename: Cruz
authors.initials: C
authors.lastname: Morenilla-Palao
authors.forename: Rosa
authors.initials: R
authors.lastname: Planells-Cases
authors.forename: Nuria
authors.initials: N
authors.lastname: García-Sanz
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferrer-Montiel
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000737:chemistry; D002460:Cell Line; D004789:Enzyme Activation; D005089:Exocytosis; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry; D008565:Membrane Proteins / Q000737:chemistry / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000737:chemistry; D011493:Protein Kinase C / Q000502:physiology*; D021381:Protein Transport; D051381:Rats; D011955:Receptors, Drug / Q000737:chemistry / Q000502:physiology*; D050600:SNARE Proteins; D050857:Synaptotagmins; D033921:Vesicular Transport Proteins
chemical_list: D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011955:Receptors, Drug; C118519:SNAPIN protein, human; D050600:SNARE Proteins; C494308:SYT9 protein, human; C498452:Snapin protein, rat; D033921:Vesicular Transport Proteins; D050857:Synaptotagmins; D011493:Protein Kinase C