Pore Helix Domain Is Critical to Camphor Sensitivity of Transient Receptor Potential Vanilloid 1 Channel

Marsakova, Lenka; Touška, Filip; Krůšek, Jan; Vlachová, Viktorie

doi:10.1097/aln.0b013e318249cf62

Cited by 15 publications

(12 citation statements)

References 56 publications

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“…Although we have not determined the mechanisms by which chloroform activates TRPV1, it is more likely than not that chloroform activates TRPV1 via a ligand gating mechanism, which would align with previous findings on VGA activation of TRP channels and the action of other membrane-partitioning compounds, such as camphor on TRPV1 activation Marsakova et al, 2012). This also corresponds with many studies that suggest that chloroform and other VGAs act on transmembrane receptors and ion channels such as the GABA receptors, NMDA receptors, and two-pore domain potassium channels via ligand receptor binding dynamic (Franks and Lieb, 1994;Franks, 2008).…”

Section: Discussionsupporting

confidence: 76%

The Pore Loop Domain of TRPV1 Is Required for Its Activation by the Volatile Anesthetics Chloroform and Isoflurane

et al. 2015

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The environmental irritant chloroform, a naturally occurring small volatile organohalogen, briefly became the world's most popular volatile general anesthetic (VGA) before being abandoned because of its low therapeutic index. When chloroform comes in contact with skin or is ingested, it causes a painful burning sensation. The molecular basis for the pain associated with chloroform remains unknown. In this study, we assessed the role of transient receptor potential (TRP) channel family members in mediating chloroform activation and the molecular determinants of VGA activation of TRPV1. We identified the subpopulation of dorsal root ganglion (DRG) neurons that are activated by chloroform. Additionally, we transiently expressed wild-type or specifically mutated TRP channels in human embryonic kidney cells and used calcium imaging or wholecell patch-clamp electrophysiology to assess the effects of chloroform or the VGA isoflurane on TRP channel activation. The results revealed that chloroform activates DRG neurons via TRPV1 activation. Furthermore, chloroform activates TRPV1, and it also activates TRPM8 and functions as a potent inhibitor of the noxious chemical receptor TRPA1. The results also indicate that residues in the outer pore region of TRPV1 previously thought to be required for either proton or heat activation of the channel are also required for activation by chloroform and isoflurane. In addition to identifying the molecular basis of DRG neuron activation by chloroform and the opposing effects chloroform has on different TRP channel family members, the findings of this study provide novel insights into the structural basis for the activation of TRPV1 by VGAs.

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Section: Discussionsupporting

confidence: 76%

The Pore Loop Domain of TRPV1 Is Required for Its Activation by the Volatile Anesthetics Chloroform and Isoflurane

et al. 2015

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“…These findings prompted us to explore whether the known proalgesic effects of bradykinin could involve a direct regulation of TRPA1 under ex vivo conditions. We used calcium imaging technique as described previously by us in (Marsakova et al 2012) and measured responses from F11 cells. In our hands, bradykinin at a concentration of 10 nM elicited large Ca 2+ transients in all naïve F11 cells (Fig.…”

Section: Putative Phosphorylation Pathways Involved In Trpa1-mediatedmentioning

confidence: 99%

Molecular Basis of TRPA1 Regulation in Nociceptive Neurons. A Review

Kádková

Synytsya²,

Krůšek³

et al. 2017

Physiol Res

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Transient receptor potential A1 (TRPA1) is an excitatory ion channel that functions as a cellular sensor, detecting a wide range of proalgesic agents such as environmental irritants and endogenous products of inflammation and oxidative stress. Topical application of TRPA1 agonists produces an acute nociceptive response through peripheral release of neuropeptides, purines and other transmitters from activated sensory nerve endings. This, in turn, further regulates TRPA1 activity downstream of G-protein and phospholipase C-coupled signaling cascades. Despite the important physiological relevance of such regulation leading to nociceptor sensitization and consequent pain hypersensitivity, the specific domains through which TRPA1 undergoes post-translational modifications that affect its activation properties are yet to be determined at a molecular level. This review aims at providing an account of our current knowledge on molecular basis of regulation by neuronal inflammatory signaling pathways that converge on the TRPA1 channel protein and through modification of its specific residues influence the extent to which this channel may contribute to pain.

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“…The pore loop of TRPA1 has been suggested to contribute to channel gating based on the finding that A946S and M949I substitutions in the upper portion of S6 segment of rat TRPA1 converted the effect of electrophilic thioaminal-containing compounds from activation to inhibition [9]. T633 in TRPV1 pore helix has also been implicated in channel gating by protons [39] and camphor [30]. Mutations in F640 and T641 of TRPV1 also led to constitutive activation and loss of proton response [31].…”

Section: Discussionmentioning

confidence: 99%

Bimodal voltage dependence of TRPA1: mutations of a key pore helix residue reveal strong intrinsic voltage-dependent inactivation

Wan

Chen

et al. 2013

Pflugers Arch - Eur J Physiol

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Transient receptor potential A1 (TRPA1) is implicated in somatosensory processing and pathological pain sensation. Although not strictly voltage-gated, ionic currents of TRPA1 typically rectify outwardly, indicating channel activation at depolarized membrane potentials. However, some reports also showed TRPA1 inactivation at high positive potentials, implicating voltage-dependent inactivation. Here we report a conserved leucine residue, L906, in the putative pore helix, which strongly impacts the voltage dependency of TRPA1. Mutation of the leucine to cysteine (L906C) converted the channel from outward to inward rectification independent of divalent cations and irrespective to stimulation by allyl isothiocyanate. The mutant, but not the wild-type channel, displayed exclusively voltage-dependent inactivation at positive potentials. The L906C mutation also exhibited reduced sensitivity to inhibition by TRPA1 blockers, HC030031 and ruthenium red. Further mutagenesis of the leucine to all natural amino acids individually revealed that most substitutions at L906 (15/19) resulted in inward rectification, with exceptions of three amino acids that dramatically reduced channel activity and one, methionine, which mimicked the wild-type channel. Our data are plausibly explained by a bimodal gating model involving both voltage-dependent activation and inactivation of TRPA1. We propose that the key pore helix residue, L906, plays an essential role in responding to the voltage-dependent gating.

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Pore Helix Domain Is Critical to Camphor Sensitivity of Transient Receptor Potential Vanilloid 1 Channel

Abstract: The findings of this study provide novel insights into the structural basis for the modulation of TRPV1 channel by camphor and may provide an explanation for the mechanism by which camphor modulates thermal sensation in vivo.

Cited by 15 publications

References 56 publications

The Pore Loop Domain of TRPV1 Is Required for Its Activation by the Volatile Anesthetics Chloroform and Isoflurane

The Pore Loop Domain of TRPV1 Is Required for Its Activation by the Volatile Anesthetics Chloroform and Isoflurane

Molecular Basis of TRPA1 Regulation in Nociceptive Neurons. A Review

Bimodal voltage dependence of TRPA1: mutations of a key pore helix residue reveal strong intrinsic voltage-dependent inactivation

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