title: Opening of an alternative ion permeation pathway in a nociceptor TRP channel.
abstract: Sensory neurons detect chemical stimuli through projections in the skin and mucosa, where several transient receptor potential (TRP) channels act as primary chemosensors. TRP channels are tetramers, and it is generally accepted that binding of ligands causes the opening of a single central cation-conducting pore. Contrary to this view, we here provide evidence for a second permeation pathway in the TRP channel TRPM3, which can be gated by combined application of endogenous neurosteroids and exogenous chemicals such as clotrimazole or several structurally related drugs. This alternative pathway is preserved following desensitization, blockade, mutagenesis and chemical modification of the central pore and enables massive Na(+) influx at negative voltages. Opening of this alternative pathway can enhance excitation of sensory neurons and thereby exacerbate TRPM3-dependent pain. Our findings indicate that a single sensory TRP channel can encompass two distinct ionotropic chemoreceptors, which may have important ramifications for TRP channel function and pharmacology.
authors.affiliation: 1] Laboratory of Ion Channel Research and TRP Research Platform Leuven (TRPLe), KU Leuven, Leuven, Belgium. [2] Laboratory of Obstetrics and Experimental Gynaecology, KU Leuven, Leuven, Belgium.
authors.forename: Joris
authors.initials: J
authors.lastname: Vriens
authors.affiliation: 1] Laboratory of Ion Channel Research and TRP Research Platform Leuven (TRPLe), KU Leuven, Leuven, Belgium. [2] Laboratory of Obstetrics and Experimental Gynaecology, KU Leuven, Leuven, Belgium. [3].
authors.forename: Katharina
authors.initials: K
authors.lastname: Held
authors.affiliation: 1] Laboratory of Ion Channel Research and TRP Research Platform Leuven (TRPLe), KU Leuven, Leuven, Belgium. [2].
authors.forename: Annelies
authors.initials: A
authors.lastname: Janssens
authors.affiliation: 1] Laboratory of Ion Channel Research and TRP Research Platform Leuven (TRPLe), KU Leuven, Leuven, Belgium. [2].
authors.forename: Balázs István
authors.initials: BI
authors.lastname: Tóth
authors.affiliation: Laboratory of Ion Channel Research and TRP Research Platform Leuven (TRPLe), KU Leuven, Leuven, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Kerselaers
authors.affiliation: Laboratory of Ion Channel Research and TRP Research Platform Leuven (TRPLe), KU Leuven, Leuven, Belgium.
authors.forename: Bernd
authors.initials: B
authors.lastname: Nilius
authors.affiliation: Laboratory of Ion Channel Research and TRP Research Platform Leuven (TRPLe), KU Leuven, Leuven, Belgium.
authors.forename: Rudi
authors.initials: R
authors.lastname: Vennekens
authors.affiliation: Laboratory of Ion Channel Research and TRP Research Platform Leuven (TRPLe), KU Leuven, Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Voets
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D003022:Clotrimazole / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007477:Ions / Q000378:metabolism; D051379:Mice; D018377:Neurotransmitter Agents / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D050053:TRPM Cation Channels / Q000187:drug effects / Q000378:metabolism*; D050051:Transient Receptor Potential Channels / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000935:Antifungal Agents; D007477:Ions; D018377:Neurotransmitter Agents; D050053:TRPM Cation Channels; C475667:TRPM3 protein, human; D050051:Transient Receptor Potential Channels; D003022:Clotrimazole