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Sci Rep. 2016 Feb 15;6:20791. doi: 10.1038/srep20791.

Selective potentiation of 2-APB-induced activation of TRPV1-3 channels by acid.

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Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX 77030.
Hefei National Laboratory of Microscale Physical Sciences, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, China.


Temperature-sensitive TRP channels are important for responses to pain and inflammation, to both of which tissue acidosis is a major contributing factor. However, except for TRPV1, acid-sensing by other ThermoTRP channels remains mysterious. We show here that unique among TRPV1-3 channels, TRPV3 is directly activated by protons from cytoplasmic side. This effect is very weak and involves key cytoplasmic residues L508, D512, S518, or A520. However, mutations of these residues did not affect a strong proton induced potentiation of TRPV3 currents elicited by the TRPV1-3 common agonist, 2-aminoethoxydiphenyl borate (2-APB), no matter if the ligand was applied from extracellular or cytoplasmic side. The acid potentiation was common among TRPV1-3 and only seen with 2-APB-related ligands. Using (1)H-nuclear magnetic resonance to examine the solution structures of 2-APB and its analogs, we observed striking structural differences of the boron-containing compounds at neutral/basic as compared to acidic pH, suggesting that a pH-dependent configuration switch of 2-APB-based drugs may underlie their functionality. Supporting this notion, protons also enhanced the inhibitory action of 2-APB on TRPM8. Collectively, our findings reveal novel insights into 2-APB action on TRP channels, which should facilitate the design of new drugs for these channels.

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