Abstract
TRPV1 receptors are polymodal cation channels that open in response to diverse stimuli including noxious heat, capsaicin, and protons. Because Ca2+ is vital for TRPV1 signaling, we sought to precisely measure its contribution to TRPV1 responses and discovered that the Ca2+ current was tuned by the mode of activation. Using patch clamp photometry, we found that the fraction of the total current carried by Ca2+ (called the Pf%) was significantly smaller for TRPV1 currents evoked by protons than for those evoked by capsaicin. Using site-directed mutagenesis, we discovered that the smaller Pf% was due to protonation of three acidic amino acids (Asp646, Glu648, and Glu651) that are located in the mouth of the pore. Thus, in keeping with recent reports of time-dependent changes in the ionic permeability of some ligand-gated ion channels, we now show for the first time that the physiologically important Ca2+ current of the TRPV1 receptor is also dynamic and depends on the mode of activation. This current is significantly smaller when the receptor is activated by a change in pH, owing to atomic scale interactions of H+ and Ca2+ with the fixed negative charge of side chains in the pore.
Highlights
The TRPV1 receptor is a member of the vanilloid subclass of the transient receptor potential family (TRP)2 of ion channel proteins [1]
We found that the fraction of the total current carried by Ca2؉ was significantly smaller for TRPV1 currents evoked by protons than for those evoked by capsaicin
We report the serendipitous discovery that proton activation of TRPV1 receptors evokes a current with a smaller Pf% than that evoked by capsaicin and that the difference results from titration of fixed negative charge in the pore
Summary
In keeping with recent reports of time-dependent changes in the ionic permeability of some ligand-gated ion channels, we show for the first time that the physiologically important Ca2؉ current of the TRPV1 receptor is dynamic and depends on the mode of activation. This current is significantly smaller when the receptor is activated by a change in pH, owing to atomic scale interactions of H؉ and Ca2؉ with the fixed negative charge of side chains in the pore. We report the serendipitous discovery that proton activation of TRPV1 receptors evokes a current with a smaller Pf% than that evoked by capsaicin and that the difference results from titration of fixed negative charge in the pore
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