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The Journal of Neuroscience, November 21, 2007, 27(47):12797-12807; doi:10.1523/JNEUROSCI.2324-07.2007

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Cellular/Molecular
Uncoupling Proton Activation of Vanilloid Receptor TRPV1

Sujung Ryu, ^* Beiying Liu, ^* Jing Yao, ^* Qiang Fu, ^* and Feng Qin

Department of Physiology and Biophysical Sciences, State University of New York at Buffalo, Buffalo, New York 14214

Correspondence should be addressed to Dr. Feng Qin, 335 Cary Hall, University at Buffalo, Buffalo, NY 14214. Email: qin{at}buffalo.edu

Multimodal gating is an essential feature of many TRP ion channels, enabling them to respond to complex cellular environments. TRPV1, a pain receptor involved in nociception at the peripheral nerve terminals, can be activated by a range of physical and chemical stimuli (e.g., capsaicin, proton, and heat) and further sensitized by proinflammatory substances. How a single receptor achieves this multiplicity of functionality is poorly understood at the molecular level. Here, we investigated the structural basis of proton activation of TRPV1. Chimeric channels between rTRPV1 and the low pH-insensitive homolog TRPV2 were constructed by systematically exchanging the extracellular domains and were characterized using whole-cell recording in transiently transfected HEK293 cells. Two discrete domains, one involving the pore helix and the other the S3–S4 linker, were found crucial for direct activation of the channel by low pH. Single residue mutations in either domain (T633A/V538L) abrogated the proton-evoked current while preserving the capsaicin and heat responses and their potentiation by mildly acidic pH. Both residues exert a gating effect through hydrophobic interactions. Our results unravel novel information on the structural basis of channel function, and support the existence of discrete domains for multimodal gating of the channel. In view of the resemblance of the pore of TRPV1 to KcsA, our findings also provide evidence on the pore helix as an active component in channel gating in addition to its role in ion permeation.

Key words: capsaicin channel; TRP channel; thermal receptor; multimodal gating; pore loop; pain

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Received May 21, 2007; revised Sept. 10, 2007; accepted Sept. 16, 2007.

Correspondence should be addressed to Dr. Feng Qin, 335 Cary Hall, University at Buffalo, Buffalo, NY 14214. Email: qin{at}buffalo.edu

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