Abstract
Transient receptor potential vanilloid 1 (TRPV1) is an ion channel that is gated by noxious heat, capsaicin and other diverse stimuli. It is a nonselective cation channel that prefers Ca2+ over Na+. These permeability characteristics, as in most channels, are widely presumed to be static. On the contrary, we found that activation of native or recombinant rat TRPV1 leads to time- and agonist concentration–dependent increases in relative permeability to large cations and changes in Ca2+ permeability. Using the substituted cysteine accessibility method, we saw that these changes were attributable to alterations in the TRPV1 selectivity filter. TRPV1 agonists showed different capabilities for evoking ionic selectivity changes. Furthermore, protein kinase C–dependent phosphorylation of Ser800 in the TRPV1 C terminus potentiated agonist-evoked ionic selectivity changes. Thus, the qualitative signaling properties of TRPV1 are dynamically modulated during channel activation, a process that probably shapes TRPV1 participation in pain, cytotoxicity and neurotransmitter release.
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Acknowledgements
We thank M. Zhu and D. Julius for providing mouse TRPV1 and 5-HT3 cDNAs, respectively, J. Wang for expert technical assistance and G. Tomaselli and members of the Caterina lab for helpful suggestions. This work was supported by grants from the US National Institutes of Health (RO1 NS051551 and RO1 NS054902), the W.M. Keck Foundation, the Arnold and Mabel Beckman Foundation and the Blaustein Pain Research Fund to M.J.C.
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All authors designed and interpreted the experiments. M.-K.C. and A.D.G. carried out the experiments, M.J.C. and M.-K.C. wrote the manuscript and M.J.C. supervised the project.
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Chung, MK., Güler, A. & Caterina, M. TRPV1 shows dynamic ionic selectivity during agonist stimulation. Nat Neurosci 11, 555–564 (2008). https://doi.org/10.1038/nn.2102
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DOI: https://doi.org/10.1038/nn.2102