A painful link between the TRPV1 channel and lysophosphatidic acid

Morales‐Lázaro, Sara L.; Rosenbaum, Tamara

doi:10.1016/j.lfs.2014.10.004

Cited by 15 publications

(10 citation statements)

References 86 publications

(104 reference statements)

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“…In contrast, LPA, an enzymatic product of lysophospholipids, produced in great amounts during tissue injury, activates TRPV1 channels by direct binding to a positively charged amino acid on the the C-terminal region of the ion channel and induces acute pain [80]. Determining the structural requirements necessary for activation by lipids similar to LPA is a necessary step to study the role of non-toxic compounds that can bind to the TRPV1 channel without producing its activation and that may potentially produce its inhibition by leading to a less active state of the channel [160].…”

Section: Pain and Inflammatory Diseasesmentioning

confidence: 99%

Lipids as central modulators of sensory TRP channels

Ciardo

Ferrer-Montiel

2017

Biochimica et Biophysica Acta (BBA) - Biomembranes

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The transient receptor potential (TRP) ion channel family is involved in a diversity of physiological processes including sensory and homeostatic functions, as well as muscle contraction and vasomotor control. Their dysfunction contributes to the etiology of several diseases, being validated as therapeutic targets. These ion channels may be activated by physical or chemical stimuli and their function is highly influenced by signaling molecules activated by extracellular signals. Notably, as integral membrane proteins, lipid molecules also modulate their membrane location and function either by direct interaction with the channel structure or by modulating the physico-chemical properties of the cellular membrane. This lipid-based modulatory effect is being considered an alternative and promising approach to regulate TRP channel dysfunction in diseases. Here, we review the current progress in this exciting field highlighting a complex channel regulation by a large diversity of lipid molecules and suggesting some diseases that may benefit from a membrane lipid therapy. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá.

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Section: Pain and Inflammatory Diseasesmentioning

confidence: 99%

Lipids as central modulators of sensory TRP channels

Ciardo

Ferrer-Montiel

2017

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…While their detailed description is beyond the scope of this review, one lipid, LPA, will be briefly discussed here, because it was proposed to activate TRPV1 via its PI(4,5)P 2 binding site [73, 76]. LPA is an extracellular signaling molecule, that exerts most of its effects via GPCRs that couple to Gq and PLC [73]. Activation of these receptors have been shown to sensitize nociceptors [73], similar to many other Gq coupled receptors.…”

Section: Dependence Of Trpv1 Activity On Phosphoinositides and Itsmentioning

confidence: 99%

“…LPA is an extracellular signaling molecule, that exerts most of its effects via GPCRs that couple to Gq and PLC [73]. Activation of these receptors have been shown to sensitize nociceptors [73], similar to many other Gq coupled receptors. In addition to this indirect effect, Nieto-Posadas et al [76] convincingly showed that 5 µM LPA also directly activates TRPV1, by demonstrating that it induces large currents via TRPV1 both in the excised inside-out and outside-out configurations.…”

Section: Dependence Of Trpv1 Activity On Phosphoinositides and Itsmentioning

confidence: 99%

Phosphoinositide regulation of TRPV1 revisited

Rohács

2015

Pflugers Arch - Eur J Physiol

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The heat- and capsaicin-sensitive Transient Receptor Potential Vanilloid 1 ion channel (TRPV1) is regulated by plasma membrane phosphoinositides. The effects of these lipids on this channel have been controversial. Recent articles re-ignited the debate and also offered resolution to place some of the data in a coherent picture. This review summarizes the literature on this topic and provides a detailed and critical discussion on the experimental evidence for the various effects of phosphatidylinositol 4,5-bisphosphayte [PI(4,5)P2 or PIP2] on TRPV1. We conclude that PI(4,5)P2 and potentially its precursor PI(4)P are positive cofactors for TRPV1, acting via direct interaction with the channel, and their depletion by Ca2+-induced activation of phospholipase Cδ isoforms (PLCδ) limits channel activity during capsaicin-induced desensitization. Other negatively charged lipids at higher concentrations can also support channel activity, which may explain some controversies in the literature. PI(4,5)P2 also partially inhibits channel activity in some experimental settings, and relief from this inhibition upon PLCβ activation may contribute to sensitization. The negative effect of PI(4,5)P2 is more controversial and its mechanism is less well understood. Other TRP channels from the TRPV and TRPC families may also undergo similar dual regulation by phosphoinositides, thus the complexity of TRPV1 regulation is not unique to this channel.

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“…Deletion of the channel region comprising residues 777-821 rendered the channel LPA insensitive, suggesting that the LPA binding site is located at the C terminus of the channel. Further charge neutralization of R701 and K710 showed that these residues, which had previously been proposed to stabilize the phosphatidylinositol 4,5-biphosphate binding pocket , are key components in LPA-dependent potentiation of TRPV1 channel activity Morales-Lázaro and Rosenbaum, 2015).…”

Section: Modulation Of Trpv1 Channel Gating By Lipidsmentioning

confidence: 88%

Structure-Driven Pharmacology of Transient Receptor Potential Channel Vanilloid 1

Díaz-Franulic

Cáceres-Molina

Sepúlveda

et al. 2016

Molecular Pharmacology

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The transient receptor potential vanilloid 1 (TRPV1) ion channel is a polymodal receptor that mediates the flux of cations across the membrane in response to several stimuli, including heat, voltage, and ligands. The best known agonist of TRPV1 channels is capsaicin, the pungent component of "hot" chili peppers. In addition, peptides found in the venom of poisonous animals, along with the lipids phosphatidylinositol 4,5-biphosphate, lysophosphatidic acid, and cholesterol, bind to TRPV1 with high affinity to modulate channel gating. Here, we discuss the functional evidence regarding ligand-dependent activation of TRPV1 channels in light of structural data recently obtained by cryoelectron microscopy. This review focuses on the mechanistic insights into ligand binding and allosteric gating of TRPV1 channels and the relevance of accurate polymodal receptor biophysical characterization for drug design in novel pain therapies.

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A painful link between the TRPV1 channel and lysophosphatidic acid

Cited by 15 publications

References 86 publications

Lipids as central modulators of sensory TRP channels

Lipids as central modulators of sensory TRP channels

Phosphoinositide regulation of TRPV1 revisited

Structure-Driven Pharmacology of Transient Receptor Potential Channel Vanilloid 1

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