Inhibition of TRPV1 channels by a naturally occurring omega-9 fatty acid reduces pain and itch

Morales‐Lázaro, Sara L.; Llorente, Itzel; Sierra-Ramírez, Félix; López-Romero, Ana E.; Ortíz-Rentería, Miguel; Serrano-Flores, Bárbara; Simon, Sidney A.; Islas, León D; Rosenbaum, Tamara

doi:10.1038/ncomms13092

Cited by 62 publications

(36 citation statements)

References 54 publications

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“…In agreement with this idea, a binding site for docosahexaenoic acid formed by an arginine residue in H + -gated GLIC channels has been identified using X-ray methods (Basak et al, 2017). In TRPV1 channels, PUFAs can interact with the channel gate or voltage sensor to open the channel or PUFAs could compete with the ligand to shut down the channel (Matta et al, 2007; Morales-Lázaro et al, 2016). In addition, oleic acid induces a pronounced rightward shift (> +100 mV) of the voltage activation of TRPV1 (Morales-Lázaro et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…In TRPV1 channels, PUFAs can interact with the channel gate or voltage sensor to open the channel or PUFAs could compete with the ligand to shut down the channel (Matta et al, 2007; Morales-Lázaro et al, 2016). In addition, oleic acid induces a pronounced rightward shift (> +100 mV) of the voltage activation of TRPV1 (Morales-Lázaro et al, 2016). In our hands, fatty acids decrease TMEM16A activity in a voltage-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

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Phosphatidylinositol 4,5-bisphosphate, cholesterol, and fatty acids modulate the calcium-activated chloride channel TMEM16A (ANO1)

Jesús-Pérez

Cruz-Rangel

Espino-Saldaña

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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The TMEM16A-mediated Ca-activated Cl current drives several important physiological functions. Membrane lipids regulate ion channels and transporters but their influence on members of the TMEM16 family is poorly understood. Here we have studied the regulation of TMEM16A by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), cholesterol, and fatty acids using patch clamp, biochemistry and fluorescence microscopy. We found that depletion of membrane PI(4,5)P2 causes a decline in TMEM16A current that is independent of cytoskeleton, but is partially prevented by removing intracellular Ca. On the other hand, supplying PI(4,5)P2 to inside-out patches attenuated channel rundown and/or partially rescued activity after channel rundown. Also, depletion (with methyl-β-cyclodextrin M-βCD) or restoration (with M-βCD+cholesterol) of membrane cholesterol slows down the current decay observed after reduction of PI(4,5)P2. Neither depletion nor restoration of cholesterol change PI(4,5)P2 content. However, M-βCD alone transiently increases TMEM16A activity and dampens rundown whereas M-βCD+cholesterol increases channel rundown. Thus, PI(4,5)P2 is required for TMEM16A function while cholesterol directly and indirectly via a PI(4,5)P2-independent mechanism regulate channel function. Stearic, arachidonic, oleic, docosahexaenoic, and eicosapentaenoic fatty acids as well as methyl stearate inhibit TMEM16A in a dose- and voltage-dependent manner. Phosphatidylserine, a phospholipid whose hydrocarbon tails contain stearic and oleic acids also inhibits TMEM16A. Finally, we show that TMEM16A remains in the plasma membrane after treatment with M-βCD, M-βCD+cholesterol, oleic, or docosahexaenoic acids. Thus, we propose that lipids and fatty acids regulate TMEM16A channels through a membrane-delimited protein-lipid interaction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol 4,5-bisphosphate, cholesterol, and fatty acids modulate the calcium-activated chloride channel TMEM16A (ANO1)

Jesús-Pérez

Cruz-Rangel

Espino-Saldaña

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…NMR spectroscopy and fluorescence/luminescence based approaches are typically the tools of choice but they cannot easily probe the motions of an ion channel when embedded in a cell membrane. This limitation is particularly severe in the case of TRPV1 whose activity shows exquisite dependency on numerous environmental factors, such as lipid composition (8,(63)(64)(65)(66)(67), extracellular concentration of Na + (11) and the presence of cholesterol or other fatty acids (68)(69)(70)(71). Accordingly, advanced experimental techniques, such as cell unroofing (72,73) and incorporation of novel unnatural amino acids (42,73), are being constantly developed to overcome these limitations and introduce only minimal perturbations to the native environment of the channel.…”

Section: Discussionmentioning

confidence: 99%

A consistent picture of TRPV1 activation emerges from molecular simulations and experiments

Yudin

et al. 2018

Preprint

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Although the structure of TRPV1 has been experimentally determined in both the closed and open states, very little is known about its activation mechanism. In particular, the conformational changes occurring in the pore domain and resulting in ionic conduction have not been identified yet. Here, we suggest a hypothetical molecular mechanism for TRPV1 activation, which involves the rotation of a conserved asparagine in S6 from the S4-S5 linker toward the pore. This rotation is correlated with the dehydration of four peripheral cavities located between S6 and the S4-S5 linker and the hydration of the pore. In light of our hypothesis, we perform bioinformatics analyses of TRP and other evolutionary related ion channels, analyze newly available structures and re-examine previously reported water accessibility and mutagenesis experiments. Overall, we provide several independent lines of evidence that corroborate our hypothesis. Finally, we show that the proposed molecular mechanism is compatible with the currently existing idea that in TRPV1 the selectivity filter acts as a secondary gate.

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“…TRPV1 integrates multiple pro-inflammatory stimuli, and for this reason, being able to modulate this pathway appears a desirable goal. For example, a natural compound, oleic acid, has recently been shown to inhibit TRPV1 activation, thus modulating pain and itch [217].…”

Section: Trpv1 Is An Extensively Studied Pain-trpmentioning

confidence: 99%

Regulation of Pain and Itch by TRP Channels

et al. 2017

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Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular sensors of chemical, thermal, and mechanical noxious stimuli to evoke the pain and itch sensations. Among them are the TRPA1 channel, members of the vanilloid subfamily (TRPV1, TRPV3, and TRPV4), and finally members of the melastatin group (TRPM2, TRPM3, and TRPM8). Given that pain and itch are pro-survival, evolutionarily-honed protective mechanisms, care has to be exercised when developing inhibitory/modulatory compounds targeting specific pain/itch-TRPs so that physiological protective mechanisms are not disabled to a degree that stimulus-mediated injury can occur. Such events have impeded the development of safe and effective TRPV1-modulating compounds and have diverted substantial resources. A beneficial outcome can be readily accomplished via simple dosing strategies, and also by incorporating medicinal chemistry design features during compound design and synthesis. Beyond clinical use, where compounds that target more than one channel might have a place and possibly have advantageous features, highly specific and high-potency compounds will be helpful in mechanistic discovery at the structure-function level.

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Inhibition of TRPV1 channels by a naturally occurring omega-9 fatty acid reduces pain and itch

Cited by 62 publications

References 54 publications

Phosphatidylinositol 4,5-bisphosphate, cholesterol, and fatty acids modulate the calcium-activated chloride channel TMEM16A (ANO1)

Phosphatidylinositol 4,5-bisphosphate, cholesterol, and fatty acids modulate the calcium-activated chloride channel TMEM16A (ANO1)

A consistent picture of TRPV1 activation emerges from molecular simulations and experiments

Regulation of Pain and Itch by TRP Channels

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