title: Cytoplasmic ankyrin repeats of transient receptor potential A1 (TRPA1) dictate sensitivity to thermal and chemical stimuli.
abstract: Transient receptor potential (TRP) channels are polymodal signal detectors that respond to a wide array of physical and chemical stimuli, making them important components of sensory systems in both vertebrate and invertebrate organisms. Mammalian TRPA1 channels are activated by chemically reactive irritants, whereas snake and Drosophila TRPA1 orthologs are preferentially activated by heat. By comparing human and rattlesnake TRPA1 channels, we have identified two portable heat-sensitive modules within the ankyrin repeat-rich aminoterminal cytoplasmic domain of the snake ortholog. Chimeric channel studies further demonstrate that sensitivity to chemical stimuli and modulation by intracellular calcium also localize to the N-terminal ankyrin repeat-rich domain, identifying this region as an integrator of diverse physiological signals that regulate sensory neuron excitability. These findings provide a framework for understanding how restricted changes in TRPA1 sequence account for evolution of physiologically diverse channels, also identifying portable modules that specify thermosensitivity.
authors.affiliation: Departments of Physiology and Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158-2517, USA.
authors.forename: Julio F
authors.initials: JF
authors.lastname: Cordero-Morales
authors.forename: Elena O
authors.initials: EO
authors.lastname: Gracheva
authors.forename: David
authors.initials: D
authors.lastname: Julius
mesh_terms: D000818:Animals; D017839:Crotalus; D003593:Cytoplasm / Q000378:metabolism; D019281:Dimerization; D029721:Drosophila Proteins / Q000737:chemistry* / Q000378:metabolism; D004331:Drosophila melanogaster; D004594:Electrophysiology / Q000379:methods; D006358:Hot Temperature; D006801:Humans; D007473:Ion Channels; D009865:Oocytes / Q000378:metabolism; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D018075:RNA, Complementary / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000737:chemistry* / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000737:chemistry* / Q000378:metabolism; D014981:Xenopus; D014982:Xenopus laevis / Q000378:metabolism; D015027:Zebrafish
chemical_list: D029721:Drosophila Proteins; D007473:Ion Channels; D018075:RNA, Complementary; D011993:Recombinant Fusion Proteins; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050051:Transient Receptor Potential Channels; C475684:TrpA1 protein, Drosophila