A molecular perspective on identifying TRPV1 thermosensitive regions and disentangling polymodal activation

Luu, Dustin D.; Owens, Aerial M.; Mebrat, Mubark D.; Horn, Wade D. Van

doi:10.1080/23328940.2021.1983354

Cited by 10 publications

(6 citation statements)

References 205 publications

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“…The complex effects of citral could also be related to findings documenting that there are several variants of the TRPV1 channel, including TRPV1b which is a naturally existing inhibitory modulator of TRPV1, and which is not activated by capsaicin and is not affected by capsazepine (Lu et al, 2005[ 36 ]; Vos et al, 2006[ 65 ]; Luu et al, 2021[ 39 ]). Therefore, it is possible in the present study that whereas capsazepine blocked the TRPV1 channel, citral acted not only on TRPV1 to reduce the activity of the TRPV1 channel but it also blocked the TRPV1b variant and thereby reduced its inhibition of the TRPV1 channel, thus making available the TRPV1 channel for capsaicin to produce a nociceptive response even in the presence of capsazepine plus citral.…”

Section: Discussionmentioning

confidence: 99%

Transient receptor potential channel involvement in antinociceptive effect of citral in orofacial acute and chronic pain models

Santos

Damasceno

Magalhães

et al. 2022

EXCLI Journal; 21:Doc869; ISSN 1611-2156

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This study aimed to test for the possible antinociceptive effect of the naturally occurring terpene citral in rodent models of acute and chronic orofacial pain and to test for the possible involvement of transient receptor potential (TRP) channels in this effect. Acute nociceptive behavior was induced in one series of experiments by administering formalin, cinnamaldehyde, menthol or capsaicin to the upper lip. Nociceptive behavior was assessed by orofacial rubbing, and the effects of pre-treatment with citral (0.1, 0.3 or 1.0 mg/Kg) or vehicle (control) were tested on the behavior. Nociceptive behavior was also induced by formalin injected into the temporomandibular joint or mustard oil injected into the masseter muscle, preceded by citral or vehicle (control) treatment. The chronic pain model involved infraorbital nerve transection (IONX) that induced mechanical hypersensitivity which was assessed by von Frey hair stimulation of the upper lip. Motor activity was also evaluated. Docking experiments were performed using TRPV1 and TRPM8 channels. Citral but not vehicle produced significant (p<0.01, ANOVA) antinociception on all the acute nociceptive behaviors, and these effects were attenuated by TRPV1 antagonist capsazepine, TRPM3 antagonist mefenamic acid and by TRPM8 desensitization, but not by ruthenium red and TRPA1 antagonist HC-030031. The IONX animals developed facial mechanical hypersensitivity that was significantly reduced by citral but not by vehicle. The docking experiments revealed that citral may interact with TRPV1 and TRPM8 channels. These results indicate the potential use of citral as an inhibitor of orofacial nociception in both acute and chronic pain states through TRPV1, TRPM3 and TRPM8 channels. See also Figure 1 (Fig. 1) .

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Section: Discussionmentioning

confidence: 99%

Transient receptor potential channel involvement in antinociceptive effect of citral in orofacial acute and chronic pain models

Santos

Damasceno

Magalhães

et al. 2022

EXCLI Journal; 21:Doc869; ISSN 1611-2156

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“…Extensive efforts have been dedicated to pinpoint the thermo-sensor elements of the thermo-TRPs. Many candidates have been evaluated through deletion, mutagenesis and chimeragenesis, so far without reaching a conclusive identification ( Diaz-Franulic et al, 2021 ; Luu et al, 2023 ). Temperature sensing elements have been proposed throughout the channel structure including: the ankyrin repeat domain for TRPA1 ( Cordero-Morales et al, 2011 ) and TRPV1 ( Saito et al, 2016 ; Ladrón-de-Guevara et al, 2020 ; Hori et al, 2023 ), a membrane proximal domain (the N-terminal region connects ankyrin repeats to the S1 helix) for TRPV1-V3 ( Yao et al, 2011 ; He et al, 2017 ; Liu and Qin, 2021 ), the whole VSLD for TRPV1 ( Kim et al, 2020 ), the pore turret ( Yang et al, 2010 ; Cui et al, 2012 ; Du et al, 2020 ) [although contradicting with a study showing the torrent-deleted TRPV1 remains thermosensitivity ( Liao et al, 2013 )], the pore helix domain for TRPV1 ( Myers et al, 2008 ) and TRPA1 ( Wang et al, 2013 ), a loop after the pore helix plus the S6 helix for TRPV3 ( Grandl et al, 2008 ), the outer pore loop region for TRPV1 ( Grandl et al, 2010 ), the whole pore domain (S5-S6) for TRPV1 ( Zhang F. et al, 2018 ) and the C-termini for TRPV1 ( Vlachová et al, 2003 ; Brauchi et al, 2006 ; Joseph et al, 2013 ).…”

Section: Molecular Mechanisms Of Trp Activation and Regulationmentioning

confidence: 99%

Targeting TRP channels: recent advances in structure, ligand binding, and molecular mechanisms

Huang,

Korsunsky,

Yazdani

et al. 2024

Front. Mol. Neurosci.

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Transient receptor potential (TRP) channels are a large and diverse family of transmembrane ion channels that are widely expressed, have important physiological roles, and are associated with many human diseases. These proteins are actively pursued as promising drug targets, benefitting greatly from advances in structural and mechanistic studies of TRP channels. At the same time, the complex, polymodal activation and regulation of TRP channels have presented formidable challenges. In this short review, we summarize recent progresses toward understanding the structural basis of TRP channel function, as well as potential ligand binding sites that could be targeted for therapeutics. A particular focus is on the current understanding of the molecular mechanisms of TRP channel activation and regulation, where many fundamental questions remain unanswered. We believe that a deeper understanding of the functional mechanisms of TRP channels will be critical and likely transformative toward developing successful therapeutic strategies targeting these exciting proteins. This endeavor will require concerted efforts from computation, structural biology, medicinal chemistry, electrophysiology, pharmacology, drug safety and clinical studies.

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“…The inherent cold activation of ancestral TRPM8 orthologs decreases stepwise, with AncVert being the least cold-sensitive ortholog. TRP channel thermosensitivity is commonly quantified by measuring the change in pseudo standard state enthalpy (ΔH) between the closed and temperature-induced open states, with negative ΔH values expected for cold sensors (50)(51)(52)(53). The cold thermosensitivity (ΔH) for the extant, AncPrim, AncMam, and AncVert are −60.4 ± 0.1, −59.8 ± 0.3, −33.0 ± 1.2, and −23.0 ± 0.1 kcal/mol, respectively.…”

Section: Ancestral Trpm8 Orthologs Traffic and Function In Human Cellsmentioning

confidence: 99%

Evidence that the cold- and menthol-sensing functions of the human TRPM8 channel evolved separately

Luu,

Ramesh,

Kazan

et al. 2024

Sci. Adv.

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Transient receptor potential melastatin 8 (TRPM8) is a temperature- and menthol-sensitive ion channel that contributes to diverse physiological roles, including cold sensing and pain perception. Clinical trials targeting TRPM8 have faced repeated setbacks predominantly due to the knowledge gap in unraveling the molecular underpinnings governing polymodal activation. A better understanding of the molecular foundations between the TRPM8 activation modes may aid the development of mode-specific, thermal-neutral therapies. Ancestral sequence reconstruction was used to explore the origins of TRPM8 activation modes. By resurrecting key TRPM8 nodes along the human evolutionary trajectory, we gained valuable insights into the trafficking, stability, and function of these ancestral forms. Notably, this approach unveiled the differential emergence of cold and menthol sensitivity over evolutionary time, providing a fresh perspective on complex polymodal behavior. These studies provide a paradigm for understanding polymodal behavior in TRPM8 and other proteins with the potential to enhance our understanding of sensory receptor biology and pave the way for innovative therapeutic interventions.

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A molecular perspective on identifying TRPV1 thermosensitive regions and disentangling polymodal activation

Cited by 10 publications

References 205 publications

Transient receptor potential channel involvement in antinociceptive effect of citral in orofacial acute and chronic pain models

Transient receptor potential channel involvement in antinociceptive effect of citral in orofacial acute and chronic pain models

Targeting TRP channels: recent advances in structure, ligand binding, and molecular mechanisms

Evidence that the cold- and menthol-sensing functions of the human TRPM8 channel evolved separately

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