Direct activation of Transient Receptor Potential Vanilloid 1(TRPV1) by Diacylglycerol (DAG). Molecular pain [Mol Pain] Journal article

ABSTRACT: Capsaicin receptor, TRPV1 (transient receptor potential channel vanilloid subtype 1), is activated by a wide range of noxious stimulants and putative ligands such as capsaicin, heat, pH, anandamide, and phosphorylation by protein kinase C (PKC). However, the identity of endogenous activators for TRPV1 under physiological condition is still debated. Here, we report that diacylglycerol (DAG) directly activates TRPV1 in a membrane-delimited manner. 1-oleoyl-2-acetyl-sn-glycerol (OAG), a membrane-permeable DAG analog, elicited intracellular Ca2+ transients, cationic currents and cobalt uptake that were blocked by TRPV1-selective antagonists, but not by inhibitors of PKC and DAG lipase. We also found that endogenously produced DAG can activate TRPV1 channels. Mutagenesis of TRPV1 revealed that DAG-binding site is at Y511, the same site for capsaicin binding, and PtdIns(4,5)P2 binding site may not be critical for the activation of TRPV1 by DAG. We propose that DAG serves as an endogenous ligand for TRPV1, acting as an integrator of Gq/11-coupled receptors linked to phospholipase C.

Molecular pain [Mol Pain]