Dataset Information

Pore dilation occurs in TRPA1 but not in TRPM8 channels.

ABSTRACT: Abundantly expressed in pain-sensing neurons, TRPV1, TRPA1 and TRPM8 are major cellular sensors of thermal, chemical and mechanical stimuli. The function of these ion channels has been attributed to their selective permeation of small cations (e.g., Ca2+, Na+ and K+), and the ion selectivity has been assumed to be an invariant fingerprint to a given channel. However, for TRPV1, the notion of invariant ion selectivity has been revised recently. When activated, TRPV1 undergoes time and agonist-dependent pore dilation, allowing permeation of large organic cations such as Yo-Pro and NMDG+. The pore dilation is of physiological importance, and has been exploited to specifically silence TRPV1-positive sensory neurons. It is unknown whether TRPA1 and TRPM8 undergo pore dilation. Here we show that TRPA1 activation by reactive or non-reactive agonists induces Yo-Pro uptake, which can be blocked by TRPA1 antagonists. In outside-out patch recordings using NMDG+ as the sole external cation and Na+ as the internal cation, TRPA1 activation results in dynamic changes in permeability to NMDG+. In contrast, TRPM8 activation does not produce either Yo-Pro uptake or significant change in ion selectivity. Hence, pore dilation occurs in TRPA1, but not in TRPM8 channels.

SUBMITTER: Chen J

PROVIDER: S-EPMC2633278 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pore dilation occurs in TRPA1 but not in TRPM8 channels.

Chen Jun J Kim Donghee D Bianchi Bruce R BR Cavanaugh Eric J EJ Faltynek Connie R CR Kym Philip R PR Reilly Regina M RM

Molecular pain 20090121

Abundantly expressed in pain-sensing neurons, TRPV1, TRPA1 and TRPM8 are major cellular sensors of thermal, chemical and mechanical stimuli. The function of these ion channels has been attributed to their selective permeation of small cations (e.g., Ca2+, Na+ and K+), and the ion selectivity has been assumed to be an invariant fingerprint to a given channel. However, for TRPV1, the notion of invariant ion selectivity has been revised recently. When activated, TRPV1 undergoes time and agonist-dep ...[more]

PMID: 19159452

Similar Datasets

Project description:The sigma 1 receptor (?1R) and the mu-opioid receptor (MOR) regulate the transient receptor potential (TRP) V1 calcium channel. A series of proteins are involved in the cross-regulation between MORs and calcium channels like the glutamate N-methyl-D-aspartate receptor (NMDAR), including the histidine triad nucleotide-binding protein 1 (HINT1), calmodulin (CaM), and the ?1R. Thus, we assessed whether similar mechanisms also apply to the neural TRP ankyrin member 1 (TRPA1), TRP vanilloid member 1 (TRPV1), and TRP melastatin member 8 (TRPM8). Our results indicate that ?1R and CaM bound directly to cytosolic regions of these TRPs, and this binding increased in the presence of calcium. By contrast, the association of HINT1 with these TRPs was moderately dependent on calcium. The ?1R always competed with CaM for binding to the TRPs, except for its binding to the TRPA1 C-terminal where ?1R binding cooperated with that of CaM. However, ?1R dampened HINT1 binding to the TRPA1 N-terminal. When the effect of ?1R ligands was addressed, the ?1R agonists PRE084 and pregnenolone sulfate enhanced the association of the ?1R with the TRPM8 N-terminal and TRPV1 C-terminal in the presence of physiological calcium, as seen for the ?1R-NMDAR interactions. However, these agonists dampened ?1R binding to the TRPA1 and TRPV1 N-terminal domains, and also to the TRPA1 C-terminal, as seen for ?1R-binding immunoglobulin protein (BiP) interactions in the endoplasmic reticulum (ER). By contrast, the ?1R antagonists progesterone and S1RA reduced the association of ?1R with TRPA1 and TRPV1 C-terminal regions, as seen for the ?1R-NMDAR interactions. Conversely, they enhanced the ?1R interaction with the TRPA1 N-terminal, as seen for ?1R-BiP interactions, whereas they barely affected the association of ?1R with the TRPV1 N-terminal. Thus, depending on the calcium channel and the cytosolic region examined, the ?1R agonists pregnenolone sulfate and PRE084 opposed or collaborated with the ?1R antagonists progesterone and S1RA to disrupt or promote such interactions. Through the use of cloned cytosolic regions of selected TRP calcium channels, we were able to demonstrate that ?1R ligands exhibit biased activity to regulate particular ?1R interactions with other proteins. Since ?1Rs are implicated in essential physiological processes, exploiting such ligand biases may represent a means to develop more selective and efficacious pharmacological interventions.

Project description:BackgroundThe cooling agents menthol and icilin act as agonists at TRPM8 and TRPA1. In vitro, activation of TRPM8 by icilin and cold, but not menthol, is dependent on the activity of a sub-type of phospholipase A2, iPLA2. Lysophospholipids (e.g. LPC) produced by PLA2 activity can also activate TRPM8. The role of TRPA1 as a primary cold sensor in vitro is controversial, although there is evidence that TRPA1 plays a role in behavioural responses to noxious cold stimuli. In this study, we have investigated the roles of TRPM8 and TRPA1 and the influence of iPLA2 on noxious cold sensitivities in naïve animals and after local administration of menthol, icilin and LPC. The roles of the channels in cold sensitivity were investigated in mice lacking either TRPM8 (Trpm8-/-) or TRPA1 (Trpa1-/-).ResultsIntraplantar administration of icilin evoked a dose-dependent increase in sensitivity to a 10 degrees C stimulus that was inhibited by iPLA2 inhibition with BEL. In contrast the cold hypersensitivities elicited by intraplantar menthol and LPC were not inhibited by BEL treatment. BEL had no effect on basal cold sensitivity and mechanical hypersensitivities induced by the TRPV1 agonist, capsaicin, and the P2X3 agonist alpha,beta-methylene ATP. Both Trpm8-/- and Trpa1-/- mice showed longer latencies for paw withdrawal from a 10 degrees C stimulus than wild-type littermates. Cold hypersensitivities induced by either icilin or LPC were absent in Trpm8-/- mice but were retained in Trpa1-/- mice. In contrast, cold hypersensitivity evoked by menthol was present in Trpm8-/- mice but was lost in Trpa1-/- mice.ConclusionsThe findings that iPLA2 inhibition blocked the development of cold hypersensitivity after administration of icilin but failed to affect menthol-induced hypersensitivity agree well with our earlier in vitro data showing a differential effect of iPLA2 inhibition on the agonist activities of these agents. The ability of LPC to induce cold hypersensitivity supports a role for iPLA2 in modulating TRPM8 activity in vivo. Studies on genetically modified mice demonstrated that the effects of icilin and LPC were mediated by TRPM8 and not TRPA1. In contrast, menthol-induced cold hypersensitivity was dependent on expression of TRPA1 and not TRPM8.

Dataset Information

Pore dilation occurs in TRPA1 but not in TRPM8 channels.

Publications

Pore dilation occurs in TRPA1 but not in TRPM8 channels.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets