title: Agonist- and Ca2+-dependent desensitization of TRPV1 channel targets the receptor to lysosomes for degradation.
abstract: TRPV1 receptor agonists such as the vanilloid capsaicin and the potent analog resiniferatoxin are well known potent analgesics. Depending on the vanilloid, dose, and administration site, nociceptor refractoriness may last from minutes up to months, suggesting the contribution of different cellular mechanisms ranging from channel receptor desensitization to Ca(2+) cytotoxicity of TRPV1-expressing neurons. The molecular mechanisms underlying agonist-induced TRPV1 desensitization and/or tachyphylaxis are still incompletely understood. Here, we report that prolonged exposure of TRPV1 to agonists induces rapid receptor endocytosis and lysosomal degradation in both sensory neurons and recombinant systems. Agonist-induced receptor internalization followed a clathrin- and dynamin-independent endocytic route, triggered by TRPV1 channel activation and Ca(2+) influx through the receptor. This process appears strongly modulated by PKA-dependent phosphorylation. Taken together, these findings indicate that TRPV1 agonists induce long-term receptor down-regulation by modulating the expression level of the channel through a mechanism that promotes receptor endocytosis and degradation and lend support to the notion that cAMP signaling sensitizes nociceptors through several mechanisms.
authors.affiliation: Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: Sanz-Salvador
authors.forename: Amparo
authors.initials: A
authors.lastname: Andrés-Borderia
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferrer-Montiel
authors.forename: Rosa
authors.initials: R
authors.lastname: Planells-Cases
mesh_terms: D000982:Antipruritics / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002211:Capsaicin / Q000494:pharmacology*; D002966:Clathrin / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D034281:Dynamins / Q000235:genetics / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009619:Nociceptors / Q000378:metabolism; D010766:Phosphorylation; D059748:Proteolysis / Q000187:drug effects*; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D050916:TRPV Cation Channels / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D000982:Antipruritics; D002966:Clathrin; D009419:Nerve Tissue Proteins; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D034281:Dynamins; D002211:Capsaicin; D002118:Calcium