Intracellular Long-Chain Acyl CoAs Activate TRPV1 Channels

Abstract

TRPV1 channels are an important class of membrane proteins that play an integral role in the regulation of intracellular cations such as calcium in many different tissue types. The anionic phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) is a known positive modulator of TRPV1 channels and the negatively charged phosphate groups interact with several basic amino acid residues in the proximal C-terminal TRP domain of the TRPV1 channel. We and other groups have shown that physiological sub-micromolar levels of long-chain acyl CoAs (LC-CoAs), another ubiquitous anionic lipid, can also act as positive modulators of ion channels and exchangers. Therefore, we investigated whether TRPV1 channel activity is similarly regulated by LC-CoAs. Our results show that LC-CoAs are potent activators of the TRPV1 channel and interact with the same PIP2-binding residues in TRPV1. In contrast to PIP2, LC-CoA modulation of TRPV1 is independent of Ca2+ i, acting in an acyl side-chain saturation and chain-length dependent manner. Elevation of LC-CoAs in intact Jurkat T-cells leads to significant increases in agonist-induced Ca2+ i levels. Our novel findings indicate that LC-CoAs represent a new fundamental mechanism for regulation of TRPV1 channel activity that may play a role in diverse cell types under physiological and pathophysiological conditions that alter fatty acid transport and metabolism such as obesity and diabetes.

Phosphoinositide regulation of TRPV1 revisited

“…Furthermore, activation of PLC upon capsaicin application was confirmed by both fluorescence based PI(4,5)P 2 and PI(4)P measurements and by demonstrating IP 3 formation in TRPV1 expressing cells [64]. Subsequent publications confirmed that PI(4,5)P 2 dialysis through the patch pipette inhibited desensitization of TRPV1 expressed in SF9 insect cells [58], and in the HEK293 derivative tsA201 cells [135]. Finally it was shown that activation of native TRPV1 by capsaicin in DRG neurons leads to depletion of PI(4,5)P 2 and PI(4)P, and that inclusion of PI(4,5)P 2 or PI(4)P in the whole cell patch pipette inhibited desensitization (Fig.…”

“…Consistent with their low charge densities, PS, PG or PI only activated TRPV1 partially, and at extremely high concentrations 250–500 µM in excised patches, close to their limit of solubility after extensive sonication [65]. Other negatively charged lipids not related to phosphoinositides, such as DGS-NTA and long acyl chain CoA (LC-CoA) also activated TRPV1 in excised patches; in line with their higher charge densities, they had larger effects and required lower concentrations than PG, PS or PI [65, 135]. …”

Lipids as central modulators of sensory TRP channels

“…Interestingly, LC-CoAs are potent activators of agonist-induced TRPV1 currents acting via a similar, but not identical, mechanism as PIP 2 by interacting with the same positively charged residues. Given the potential role of inflammation in the etiology of certain metabolic disorders such as obesity and diabetes, that display altered fatty acid metabolism and transport and where dietary consumption of saturated fatty acids is a determining factor, increased LC-CoA-mediated TRPV1 channel activation may be a contributing mechanism [141].…”

TRP channels interaction with lipids and its implications in disease

“…Furthermore, some potent TRP agonists are lipids. The effect of lipids on TRP channels function has attracted the interest of the pharmaceutical industry and the academic research, as reflected by the number of research articles and reviews of this field [19][20][21][22][23].…”