title: TRPA1 is differentially modulated by the amphipathic molecules trinitrophenol and chlorpromazine.
abstract: TRPA1, a poorly selective Ca(2+)-permeable cation channel, is expressed in peripheral sensory neurons, where it is considered to contribute to a variety of sensory processes such as the detection of painful stimuli. Furthermore, TRPA1 was also identified in hair cells of the inner ear, but its involvement in sensing mechanical forces is still being controversially discussed. Amphipathic molecules such as trinitrophenol and chlorpromazine have been shown to provide useful tools to study mechanosensitive channels. Depending on their charge, they partition in the inner or outer sheets of the lipid bilayer, causing a curvature of the membrane, which has been demonstrated to activate or inhibit mechanosensitive ion channels. In the present study, we investigated the effect of these molecules on TRPA1 gating. TRPA1 was robustly activated by the anionic amphipathic molecule trinitrophenol. The whole-cell and single channel properties resemble those previously described for TRPA1. Moreover, we could show that the toxin GsMTx-4 acts on TRPA1. In addition to its recently described role as an inhibitor of stretch-activated ion channels, it serves as a potent activator of TRPA1 channels. On the other hand, the positively charged drug chlorpromazine modulates activated TRPA1 currents in a voltage-dependent way. The exposure of activated TRPA1 channels to chlorpromazine led to a block at positive potentials and an increased open probability at negative potentials. The variability in the shape of the I-V curve gives a first indication that native mechanically activated TRPA1 currents must not necessarily exhibit the same biophysical properties as ligand-activated TRPA1 currents.
authors.affiliation: Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Thielallee 67-73, 14195 Berlin, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hill
authors.forename: Michael
authors.initials: M
authors.lastname: Schaefer
mesh_terms: D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002746:Chlorpromazine / Q000494:pharmacology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D017879:Isothiocyanates / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000502:physiology; D010455:Peptides / Q000494:pharmacology; D010851:Picrates / Q000494:pharmacology*; D051571:Protein Kinase C-alpha / Q000378:metabolism; D013111:Spider Venoms / Q000494:pharmacology; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000187:drug effects* / Q000502:physiology
chemical_list: D015220:Calcium Channels; D036341:Intercellular Signaling Peptides and Proteins; D017879:Isothiocyanates; C411249:MTx4 protein, Grammostola spatulata; D009419:Nerve Tissue Proteins; D010455:Peptides; D010851:Picrates; D013111:Spider Venoms; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050051:Transient Receptor Potential Channels; C005858:picric acid; C004471:allyl isothiocyanate; D051571:Protein Kinase C-alpha; D002118:Calcium; D002746:Chlorpromazine