Tunable Calcium Current through TRPV1 Receptor Channels

• Published in: The Journal of biological chemistry 2008-11, Vol.283 (46), p.31274-31278
• Main Authors: Samways, Damien S.K., Khakh, Baljit S., Egan, Terrance M.
• Format: Article
• Language: English
• Subjects: Animals; Calcium - metabolism; Cell Line; Humans; Membrane Potentials - drug effects; Mutation - genetics; Rats; TRPV Cation Channels - agonists; TRPV Cation Channels - genetics; TRPV Cation Channels - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.C800131200

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.