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. 2012 Aug 9:3:324.
doi: 10.3389/fphys.2012.00324. eCollection 2012.

TRP channels: sensors and transducers of gasotransmitter signals

Nobuaki Takahashi  1 , Daisuke Kozai, Yasuo Mori
Affiliations

TRP channels: sensors and transducers of gasotransmitter signals

Nobuaki Takahashi et al. Front Physiol. .

Abstract

The transient receptor potential (trp) gene superfamily encodes cation channels that act as multimodal sensors for a wide variety of stimuli from outside and inside the cell. Upon sensing, they transduce electrical and Ca(2+) signals via their cation channel activities. These functional features of TRP channels allow the body to react and adapt to different forms of environmental changes. Indeed, members of one class of TRP channels have emerged as sensors of gaseous messenger molecules that control various cellular processes. Nitric oxide (NO), a vasoactive gaseous molecule, regulates TRP channels directly via cysteine (Cys) S-nitrosylation or indirectly via cyclic GMP (cGMP)/protein kinase G (PKG)-dependent phosphorylation. Recent studies have revealed that changes in the availability of molecular oxygen (O(2)) also control the activation of TRP channels. Anoxia induced by O(2)-glucose deprivation and severe hypoxia (1% O(2)) activates TRPM7 and TRPC6, respectively, whereas TRPA1 has recently been identified as a novel sensor of hyperoxia and mild hypoxia (15% O(2)) in vagal and sensory neurons. TRPA1 also detects other gaseous molecules such as hydrogen sulfide (H(2)S) and carbon dioxide (CO(2)). In this review, we focus on how signaling by gaseous molecules is sensed and integrated by TRP channels.

Keywords: TRP channels; TRPA1; TRPC5; TRPC6; TRPV1; gasotransmitter; nitric oxide; oxygen.

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Figures

Figure 1
Figure 1
Transmembrane topology and phylogenetic tree of mammalian TRP channels. (A) Transmembrane topology (left) and the quartenary structure of TRP channels (right). The TRP protein has six putative transmembrane domains, a pore region between the fifth and sixth transmembrane domains and a TRP domain in the C-terminal region. The TRP protein assembles into homo-tetramers or hetero-tetramers to form channels. (B) Phylogenetic tree of mammalian TRP channels based on their homology.
Figure 2
Figure 2
A sensing mechanism for gaseous molecules linked to metabolic pathways. TRP channels mediate sensing mechanism for H2S, O2 (anoxia, hypoxia, or hyperoxia), NO, and CO2.
Figure 3
Figure 3
Model for activation of TRPC5 channel by NO. Cys553 is nitrosylated by NO, which triggers TRPC5 channel opening. The free sulfhydryl group of Cys558 nucleophilically attacks nitrosylated Cys553 to form a disulfide bond that stabilizes the open state.
Figure 4
Figure 4
Model for TRPC5-mediated feedback of Ca2+ and NO signaling in endothelial cells and attenuation of Ca2+ entry through TRPC6 by NO in smooth muscle cells. Stimulation of G protein-coupled receptors (GPCRs) (such as the ATP-activated P2Y receptor) induces Ca2+ influx and activation of eNOS as a consequence of binding of Ca2+-CaM and release of eNOS from caveolin-1. TRPC5 undergoes eNOS-dependent S-nitrosylation after GPCR stimulation, resulting in amplified Ca2+ entry and secondary activation of eNOS to amplify production of NO. NO diffuses out of endothelial cells into adjacent smooth muscle cells and stimulates the guanylate cyclase, which leads to the activation of PKG in smooth muscle cells. In the most prevailing hypothesis, the magnitude of continuous Ca2+ influx through VDCC, which critically determines the contractile status of vascular smooth muscle cells, decreases and increases by membrane hyperpolarization and depolarization, respectively. TRPC6 likely functions as a depolarization (Δψ)-inducing channel or a direct Ca2+-entry pathway, activated in response to receptor stimulation. The NO/cGMP/PKG pathway suppresses TRPC6 and VDCC activity to induce relaxation of smooth muscle.
Figure 5
Figure 5
Model for O2-sensing of TRPA1 channel. PHDs hydroxylate specific Pro residue on the N-terminal AnkR domain of TRPA1 protein in normoxia, whereas a decrease in O2 concentrations diminishes PHD activity and relieves TRPA1 from the hydroxylation, leading to its activation in hypoxia. The relief can be achieved by insertion of unmodified TRPA1 proteins into the plasma membrane or by dehydroxylation through an unidentified molecular mechanism. In hyperoxia, O2 oxidizes specific Cys residues, thereby activating TRPA1. TRPA1 may at least take two oxidized state upon hyperoxia: a relatively unstable oxidized state (state 1) readily reversed by glutathione and a relatively stable oxidized state (state 2). Sulfhydryl group(s) of the key Cys residues may be modified to sulfenic acid in the former state of TRPA1, whereas that in the latter state of TRPA1 may form a disulfide bond(s). These oxidation mechanisms over-ride the inhibition by Pro hydroxylation to activate TRPA1.
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