Different agonists induce distinct single-channel conductance states in TRPV1 channels

The TRPV1 ion channel is a membrane protein that is expressed in primary afferent nociceptors, where it is activated by a diverse array of stimuli. Our prior work has shown that this channel is activated by lysophosphatidic acid (LPA), an unsaturated lysophospholipid that is produced endogenously and released under certain pathophysiological conditions, resulting in the sensation of pain. Macroscopic currents activated by saturating concentrations of LPA applied to excised membrane patches are larger in magnitude than those activated by saturating concentrations of capsaicin, which causes near-maximal TRPV1 open probability. Here we show that activation of TRPV1 by LPA is associated with a higher single-channel conductance than activation by capsaicin. We also observe that the effects of LPA on TRPV1 are not caused by an increase in the surface charge nor are they mimicked by a structurally similar lipid, ruling out the contribution of change in membrane properties. Finally, we demonstrate that the effects of LPA on the unitary conductance of TRPV1 depend upon the presence of a positively charged residue in the C terminus of the channel, suggesting that LPA induces a distinct conformational change.