title: Activation characteristics of transient receptor potential ankyrin 1 and its role in nociception.
abstract: Transient receptor potential (TRP) ankyrin 1 (TRPA1) is a Ca(2+)-permeant, nonselective cationic channel. It is predominantly expressed in the C afferent sensory nerve fibers of trigeminal and dorsal root ganglion neurons and is highly coexpressed with the nociceptive ion channel transient receptor potential vanilloid 1 (TRPV1). Several physical and chemical stimuli have been shown to activate the channel. In this study, we have used electrophysiological techniques and behavioral models to characterize the properties of TRPA1. Whole cell TRPA1 currents induced by brief application of lower concentrations of N-methyl maleimide (NMM) or allyl isothiocyanate (AITC) can be reversed readily by washout, whereas continuous application of higher concentrations of NMM or AITC completely desensitized the currents. The deactivation and desensitization kinetics differed between NMM and AITC. TRPA1 current amplitude increased with repeated application of lower concentrations of AITC, whereas saturating concentrations of AITC induced tachyphylaxis, which was more pronounced in the presence of extracellular Ca(2+). The outward rectification exhibited by native TRPA1-mediated whole cell and single-channel currents was minimal as compared with other TRP channels. TRPA1 currents were negatively modulated by protons and polyamines, both of which activate the heat-sensitive channel, TRPV1. Interestingly, neither protein kinase C nor protein kinase A activation sensitized AITC-induced currents, but each profoundly sensitized capsaicin-induced currents. Current-clamp experiments revealed that AITC produced a slow and sustained depolarization as compared with capsaicin. TRPA1 is also expressed at the central terminals of nociceptors at the caudal spinal trigeminal nucleus. Activation of TRPA1 in this area increases the frequency and amplitude of miniature excitatory or inhibitory postsynaptic currents. In behavioral studies, intraplantar and intrathecal administration of AITC induced more pronounced and prolonged changes in nociceptive behavior than those induced by capsaicin. In conclusion, the characteristics of TRPA1 we have delineated suggest that it might play a unique role in nociception.
authors.affiliation: Dept. of Pharmacology, Southern Illinois Univ. School of Medicine, Springfield, IL 62702, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Raisinghani
authors.forename: Linlin
authors.initials: L
authors.lastname: Zhong
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Jeffry
authors.forename: Mahendra
authors.initials: M
authors.lastname: Bishnoi
authors.forename: Reddy M
authors.initials: RM
authors.lastname: Pabbidi
authors.forename: Fátima
authors.initials: F
authors.lastname: Pimentel
authors.forename: De-Shou
authors.initials: DS
authors.lastname: Cao
authors.forename: M Steven
authors.initials: MS
authors.lastname: Evans
authors.forename: Louis S
authors.initials: LS
authors.lastname: Premkumar
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000498:Allyl Compounds / Q000494:pharmacology; D000818:Animals; D017487:Ankyrins / Q000819:agonists / Q000502:physiology*; D001522:Behavior, Animal / Q000187:drug effects; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D002211:Capsaicin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena / Q000187:drug effects / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005727:Ganglia, Spinal / Q000166:cytology; D006863:Hydrogen-Ion Concentration; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D015640:Ion Channel Gating / Q000187:drug effects; D017953:Isocyanates / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D059225:Nociception / Q000502:physiology*; D059226:Nociceptive Pain / Q000139:chemically induced / Q000503:physiopathology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013096:Spermine / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050916:TRPV Cation Channels / Q000235:genetics; D013618:Tachyphylaxis / Q000502:physiology; D050051:Transient Receptor Potential Channels / Q000819:agonists / Q000502:physiology*; D014275:Trigeminal Caudal Nucleus / Q000166:cytology; D014982:Xenopus laevis
chemical_list: D000498:Allyl Compounds; D017487:Ankyrins; D015220:Calcium Channels; D017953:Isocyanates; D008301:Maleimides; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C480976:Trpa1 protein, rat; C491149:allyl isocyanate; D005576:Colforsin; D013096:Spermine; D015240:Phorbol 12,13-Dibutyrate; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; C527323:N-methylmaleimide; D002211:Capsaicin; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine