Abstract
The capsaicin receptor (TRPV1) is a nonselective cation channel that integrates multiple painful stimuli, including capsaicin, protons and heat. Protons facilitate the capsaicin- and heat -induced currents by decreasing thermal threshold or increasing agonist potency for TRPV1 activation. In the presence of saturating capsaicin, rat TRPV1 (rTRPV1) reaches full activation, with no further stimulation by protons. Human TRPV1 (hTRPV1), a species ortholog with high homology to rTPRV1, is potentiated by extracellular protons and magnesium, even at saturating capsaicin. We investigated the structural basis for protons and magnesium modulation of fully capsaicin-bound human receptors. By analysis of chimeric channels between hTRPV1 and rTRPV1,We mapped the required domain and a single amino acid residue responsible for further potentiation of capsaicin efficacy by protons. We also showed that magnesium ions could also exert similar effects for capsaicin activation of human TRPV1, but through a different functional domain. Our results demonstrate that capsaicin efficacy of hTRPV1 correlates with the extracellular ion milieu, and unravel the relevant structural basis of modulation by protons and magnesium.
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