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.
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Acknowledgements
We thank all members of the Laboratory of Ion Channel Research for helpful discussions. We thank the Cell Banking Facility of the Physiology Department at the Institute of Functional Genomics (Montpellier, France) for the F11 cell line. This work was supported by grants from the Belgian Federal Government (IUAP P7/13 to T.V.), the Research Foundation-Flanders (G.0565.07 and G.0825.11 to T.V. and J.V.), the Research Council of the KU Leuven (GOA 2009/07 and PF-TRPLe to T.V. and R.V.), the Planckaert-De Waele fund (to J.V.) and by a Marie Curie Intra-European Fellowship within the Seventh European Community Framework Programme (to B.I.T.).
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J.V. and T.V. designed the project strategy and wrote the manuscript. J.V., K.H., A.J., B.I.T., S.K. and T.V. conducted and analyzed experiments. J.V., B.N., R.V. and T.V. supervised the project.
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Vriens, J., Held, K., Janssens, A. et al. Opening of an alternative ion permeation pathway in a nociceptor TRP channel. Nat Chem Biol 10, 188–195 (2014). https://doi.org/10.1038/nchembio.1428
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DOI: https://doi.org/10.1038/nchembio.1428
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