The major differences between the effects of LC-CoAs and PIP2 reside in 1) the process of TRPV1 channel desensitization and 2) voltage-dependence. Upon repeated exposure to agonists such as capsaicin or acidic pH, TRPV1 channels experience almost complete desensitization. This desensitization mechanism is suggested to negatively regulate channel activity to limit excessive Ca2+entry. Desensitization involves Ca2+ dependent activation of PLC-mediated PIP2 depletion from the plasma membrane. Previous work has shown that the application of PIP2 to insideout excised patches rescues TRPV1 from the desensitized state. Our data also show that palmitoyl CoA can similarly rescue TRPV1 channels from the desensitized state following repeated application of either capsaicin or a pH 5.5 solution. We also show that the magnitude of the PIP2 and LC-CoA stimulatory effect are similar and not additive, suggesting that they may be interacting at the same site on the TRPV1 channel. However, unlike PIP2, the LC-CoA modulation of TRPV1 channels is Ca2+ independent. Our results also suggest that LC-CoAs are interacting with the PIP2 binding site in a competitive manner. Importantly, as the LC-CoA effect is Ca2+independent and not susceptible to PLC-mediated cleavage, sustained increases in unbound intracellular LC-CoA levels may lead to TRPV1 channel over-activity and detrimental cellular Ca2+ loading. The putative LC-CoA binding site is of obvious importance. Previous investigations have suggested that PIP2 interacts with residues in the C-terminus of the TRPV1 channel. It has previously been shown that PIP2 interacts with two basic amino acids in the proximal C-terminal TRP domain; R701 and K710 in the rat TRPV1 channel. Recent resolution of the TRPV1 channel to determined by electron cryo-microscopy suggest these charged residues in the helical TRP domain are adjacent to the cytoplasmic-membrane interface and are ideally positioned to interact with lipid modulators. In addition, the helical TRP domain interacts with the S4-S5 and S5-P-S6 domains known to be involved in channel gating and all three structures are displaced in the partially activated state when compared to the channels apo conformation. These data indicate that the TRP domain may be acting as a sliding helix and control gating in a similar manner to that observed in some potassium channels. It has been previously proposed that the anionic head group of PIP2 interacts with R701 while K710 stabilizes the PIP2 binding region without making any direct PIP2 contact. We therefore investigated the analogous residues in the human TRPV1 channel. Our data suggests that both of these PIP2-interacting residues also play a role in LCCoA modulation. As the kinetic parameters of the K711A current were indistinguishable from the WT channel in the absence of PIP2, we propose that K711 directly interacts with LCCoAs.