title: TRPM3 is a nociceptor channel involved in the detection of noxious heat.
abstract: Transient receptor potential melastatin-3 (TRPM3) is a broadly expressed Ca(2+)-permeable nonselective cation channel. Previous work has demonstrated robust activation of TRPM3 by the neuroactive steroid pregnenolone sulfate (PS), but its in vivo gating mechanisms and functions remained poorly understood. Here, we provide evidence that TRPM3 functions as a chemo- and thermosensor in the somatosensory system. TRPM3 is molecularly and functionally expressed in a large subset of small-diameter sensory neurons from dorsal root and trigeminal ganglia, and mediates the aversive and nocifensive behavioral responses to PS. Moreover, we demonstrate that TRPM3 is steeply activated by heating and underlies heat sensitivity in a subset of sensory neurons. TRPM3-deficient mice exhibited clear deficits in their avoidance responses to noxious heat and in the development of inflammatory heat hyperalgesia. These experiments reveal an unanticipated role for TRPM3 as a thermosensitive nociceptor channel implicated in the detection of noxious heat.
authors.affiliation: Laboratory of Ion Channel Research and TRP Research Platform Leuven (TRPLe), KU Leuven, 3000 Leuven, Belgium. joris.vriens@med.kuleuven.be
authors.forename: Joris
authors.initials: J
authors.lastname: Vriens
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Owsianik
authors.forename: Thomas
authors.initials: T
authors.lastname: Hofmann
authors.forename: Stephan E
authors.initials: SE
authors.lastname: Philipp
authors.forename: Julia
authors.initials: J
authors.lastname: Stab
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Chen
authors.forename: Melissa
authors.initials: M
authors.lastname: Benoit
authors.forename: Fenqin
authors.initials: F
authors.lastname: Xue
authors.forename: Annelies
authors.initials: A
authors.lastname: Janssens
authors.forename: Sara
authors.initials: S
authors.lastname: Kerselaers
authors.forename: Johannes
authors.initials: J
authors.lastname: Oberwinkler
authors.forename: Rudi
authors.initials: R
authors.lastname: Vennekens
authors.forename: Thomas
authors.initials: T
authors.lastname: Gudermann
authors.forename: Bernd
authors.initials: B
authors.lastname: Nilius
authors.forename: Thomas
authors.initials: T
authors.lastname: Voets
mesh_terms: D000178:Acrylamides / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects / Q000235:genetics; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005620:Freund's Adjuvant / Q000009:adverse effects; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000235:genetics / Q000528:radiation effects; D006358:Hot Temperature / Q000009:adverse effects*; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009149:Mustard Plant; D009543:Nifedipine / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010938:Plant Oils / Q000494:pharmacology; D011284:Pregnenolone / Q000009:adverse effects; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D000074025:TRPA1 Cation Channel; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013686:Telemetry / Q000379:methods; D013997:Time Factors; D014162:Transfection / Q000379:methods; D050051:Transient Receptor Potential Channels / Q000172:deficiency / Q000235:genetics; D012668:Trigeminal Ganglion / Q000166:cytology
chemical_list: C500530:3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo(b)(1,4)dioxin-6-yl)acrylamide; D000178:Acrylamides; D001786:Blood Glucose; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002121:Calcium Channel Blockers; D010938:Plant Oils; D000074025:TRPA1 Cation Channel; D050053:TRPM Cation Channels; C533868:TRPM3 protein, mouse; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C018370:pregnenolone sulfate; D011284:Pregnenolone; D005620:Freund's Adjuvant; D009543:Nifedipine; D002211:Capsaicin; D002118:Calcium; C027793:mustard oil