Structural determinants of the transient receptor potential 1 (TRPV1) channel activation by phospholipid analogs

Sara L. Morales-Lázaro, Barbara Serrano-Flores, Itzel Llorente, Enrique Hernández-García, Ricardo González-Ramírez, Souvik Banerjee, Duane Miller, Veeresh Gududuru, James Fells, Derek Norman, Gabor Tigyi, Diana Escalante-Alcalde, Tamara Rosenbaum

Research output: Contribution to journalArticle

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Abstract

The transient receptor potential vanilloid 1 (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 close to 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, 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 with LPA G-protein-coupled receptors. We synthesized fatty alcohol phosphates and thiophosphates and found that many of them with a single double bond in position Δ9, 10, or 11 and Δ9 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.

Original languageEnglish (US)
Pages (from-to)24079-24090
Number of pages12
JournalJournal of Biological Chemistry
Volume289
Issue number35
DOIs
StatePublished - Jan 1 2014

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Phospholipids
Chemical activation
Lipids
Capsaicin
Fatty Alcohols
vanilloid receptor subtype 1
Capsicum
Nociceptors
Phosphatidic Acids
Neuralgia
G-Protein-Coupled Receptors
Hydrocarbons
Ion Channels
Chain length
lysophosphatidic acid
Phosphates
Ligands
Temperature
Acids
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Morales-Lázaro, S. L., Serrano-Flores, B., Llorente, I., Hernández-García, E., González-Ramírez, R., Banerjee, S., ... Rosenbaum, T. (2014). Structural determinants of the transient receptor potential 1 (TRPV1) channel activation by phospholipid analogs. Journal of Biological Chemistry, 289(35), 24079-24090. https://doi.org/10.1074/jbc.M114.572503

Structural determinants of the transient receptor potential 1 (TRPV1) channel activation by phospholipid analogs. / Morales-Lázaro, Sara L.; Serrano-Flores, Barbara; Llorente, Itzel; Hernández-García, Enrique; González-Ramírez, Ricardo; Banerjee, Souvik; Miller, Duane; Gududuru, Veeresh; Fells, James; Norman, Derek; Tigyi, Gabor; Escalante-Alcalde, Diana; Rosenbaum, Tamara.

In: Journal of Biological Chemistry, Vol. 289, No. 35, 01.01.2014, p. 24079-24090.

Research output: Contribution to journalArticle

Morales-Lázaro, SL, Serrano-Flores, B, Llorente, I, Hernández-García, E, González-Ramírez, R, Banerjee, S, Miller, D, Gududuru, V, Fells, J, Norman, D, Tigyi, G, Escalante-Alcalde, D & Rosenbaum, T 2014, 'Structural determinants of the transient receptor potential 1 (TRPV1) channel activation by phospholipid analogs', Journal of Biological Chemistry, vol. 289, no. 35, pp. 24079-24090. https://doi.org/10.1074/jbc.M114.572503
Morales-Lázaro SL, Serrano-Flores B, Llorente I, Hernández-García E, González-Ramírez R, Banerjee S et al. Structural determinants of the transient receptor potential 1 (TRPV1) channel activation by phospholipid analogs. Journal of Biological Chemistry. 2014 Jan 1;289(35):24079-24090. https://doi.org/10.1074/jbc.M114.572503
Morales-Lázaro, Sara L. ; Serrano-Flores, Barbara ; Llorente, Itzel ; Hernández-García, Enrique ; González-Ramírez, Ricardo ; Banerjee, Souvik ; Miller, Duane ; Gududuru, Veeresh ; Fells, James ; Norman, Derek ; Tigyi, Gabor ; Escalante-Alcalde, Diana ; Rosenbaum, Tamara. / Structural determinants of the transient receptor potential 1 (TRPV1) channel activation by phospholipid analogs. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 35. pp. 24079-24090.
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