title: The ubiquitin ligase MYCBP2 regulates transient receptor potential vanilloid receptor 1 (TRPV1) internalization through inhibition of p38 MAPK signaling.
abstract: The E3 ubiquitin ligase MYCBP2 negatively regulates neuronal growth, synaptogenesis, and synaptic strength. More recently it was shown that MYCBP2 is also involved in receptor and ion channel internalization. We found that mice with a MYCBP2-deficiency in peripheral sensory neurons show prolonged thermal hyperalgesia. Loss of MYCBP2 constitutively activated p38 MAPK and increased expression of several proteins involved in receptor trafficking. Surprisingly, loss of MYCBP2 inhibited internalization of transient receptor potential vanilloid receptor 1 (TRPV1) and prevented desensitization of capsaicin-induced calcium increases. Lack of desensitization, TRPV internalization and prolonged hyperalgesia were reversed by inhibition of p38 MAPK. The effects were TRPV-specific, since neither mustard oil-induced desensitization nor behavioral responses to mechanical stimuli were affected. In summary, we show here for the first time that p38 MAPK activation can inhibit activity-induced ion channel internalization and that MYCBP2 regulates internalization of TRPV1 in peripheral sensory neurons as well as duration of thermal hyperalgesia through p38 MAPK.
authors.affiliation: Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES, Klinikum der Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Holland
authors.forename: Ovidiu
authors.initials: O
authors.lastname: Coste
authors.forename: Dong Dong
authors.initials: DD
authors.lastname: Zhang
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Pierre
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Klaus
authors.initials: K
authors.lastname: Scholich
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D004705:Endocytosis; D006930:Hyperalgesia / Q000209:etiology; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D011984:Sensory Receptor Cells; D050916:TRPV Cation Channels / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D002352:Carrier Proteins; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C532954:Mycbp2 protein, mouse; D044767:Ubiquitin-Protein Ligases; D048051:p38 Mitogen-Activated Protein Kinases