title: Pore dilation occurs in TRPA1 but not in TRPM8 channels.
abstract: Abundantly expressed in pain-sensing neurons, TRPV1, TRPA1 and TRPM8 are major cellular sensors of thermal, chemical and mechanical stimuli. The function of these ion channels has been attributed to their selective permeation of small cations (e.g., Ca2+, Na+ and K+), and the ion selectivity has been assumed to be an invariant fingerprint to a given channel. However, for TRPV1, the notion of invariant ion selectivity has been revised recently. When activated, TRPV1 undergoes time and agonist-dependent pore dilation, allowing permeation of large organic cations such as Yo-Pro and NMDG+. The pore dilation is of physiological importance, and has been exploited to specifically silence TRPV1-positive sensory neurons. It is unknown whether TRPA1 and TRPM8 undergo pore dilation. Here we show that TRPA1 activation by reactive or non-reactive agonists induces Yo-Pro uptake, which can be blocked by TRPA1 antagonists. In outside-out patch recordings using NMDG+ as the sole external cation and Na+ as the internal cation, TRPA1 activation results in dynamic changes in permeability to NMDG+. In contrast, TRPM8 activation does not produce either Yo-Pro uptake or significant change in ion selectivity. Hence, pore dilation occurs in TRPA1, but not in TRPM8 channels.
authors.affiliation: Neuroscience, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6125, USA. jun.x.chen@abbott.com
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Donghee
authors.initials: D
authors.lastname: Kim
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Bianchi
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Cavanaugh
authors.forename: Connie R
authors.initials: CR
authors.lastname: Faltynek
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
authors.forename: Regina M
authors.initials: RM
authors.lastname: Reilly
mesh_terms: D000447:Aldehydes / Q000494:pharmacology; D000498:Allyl Compounds / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001583:Benzoxazoles / Q000493:pharmacokinetics; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology; D002219:Carbamates / Q000494:pharmacology; D002478:Cells, Cultured; D006367:HeLa Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D008012:Lidocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009068:Movement / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D018272:Porins / Q000378:metabolism*; D011806:Quinolinium Compounds / Q000493:pharmacokinetics; D051381:Rats; D000074025:TRPA1 Cation Channel; D050053:TRPM Cation Channels / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D013861:Thiocyanates / Q000494:pharmacology; D050051:Transient Receptor Potential Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*
chemical_list: D000447:Aldehydes; D000498:Allyl Compounds; D000779:Anesthetics, Local; D001549:Benzamides; D001583:Benzoxazoles; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002219:Carbamates; D009419:Nerve Tissue Proteins; D018272:Porins; D011806:Quinolinium Compounds; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D013861:Thiocyanates; D050051:Transient Receptor Potential Channels; C491148:allyl thiocyanate; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C089813:YO-PRO 1; C012647:QX-314; D008012:Lidocaine; C027576:4-hydroxy-2-nonenal; D002118:Calcium