structural determinants of the transient receptor potential 1 (TRPV1) channel activation by phospholipid analogs [Molecular Biophysics]

July 17th, 2014 by Morales-Lazaro, S. L., Serrano-Flores, B., Llorente, I., Hernandez-Garcia, E., Gonzalez-Ramirez, R., Banerjee, S., Miller, D., Gududuru, V., Fells, J., Norman, D., Tigyi, G., Escalante-Alcalde, D., Rosenbaum, T.

The TRPV1 ion channel is a polymodal protein that responds to various stimuli, including capsaicin (the pungent compound found in chili peppers), extracellular acid and basic intracellular pH, temperatures near 42 C, and several lipids. Lysophosphatidic acid (LPA), an endogenous lipid widely associated with neuropathic pain, is an agonist of the TRPV1 channel found in primary afferent nociceptors and is activated by other noxious stimuli. Agonists or antagonists of lipid and other chemical natures are known to possess specific structural requirements for producing functional effects on their targets. To better understand how LPA and other lipid analogs might interact and affect the function of TRPV1, we set out to determine the structural features of these lipids that result in the activation of TRPV1. By changing the acyl chain length and saturation and headgroup of these LPA analogs, we established strict requirements for activation of TRPV1. Among the natural LPA analogs we found that only LPA 18:1, alkylglycerophosphate 18:1 and cyclic-phosphatidic acid 18:1, all with a monounsaturated C18 hydrocarbon chain activate TRPV1, whereas polyunsaturated and saturated analogs do not. Thus TRPV1 shows a more restricted ligand specificity compared to LPA GPCRs. We synthesized fatty alcohol phosphates and thiophosphates and found that many of them with a single double bond in position ∆9, 10, or 11 and ∆9 cyclopropyl group can activate TRPV1 with efficacy similar to capsaicin. Finally, we developed a pharmacophore and proposed a mechanistic model for how these lipids could induce a conformational change that activates TRPV1.