期刊
NATURE CHEMICAL BIOLOGY
卷 10, 期 3, 页码 188-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1428
关键词
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资金
- Belgian Federal Government [IUAP P7/13]
- Research Foundation-Flanders [G.0565.07, G.0825.11]
- Research Council of the KU Leuven [GOA 2009/07]
- Planckaert-De Waele fund
- Marie Curie Intra-European Fellowship within the Seventh European Community Framework Programme
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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