TRP Channels as Sensors and Signal Integrators of Redox Status Changes

Abstract

Proteins are capable of sensing the redox status of cells. Cysteine residues, which react with oxidants, reductants, and electrophiles, have been increasingly recognized as the mediators of this redox sensitivity. Cation channels encoded by the transient receptor potential (trp) gene superfamily are characterized by a wide variety of activation triggers that act from outside and inside the cell. Recent studies have revealed that a class of TRP channels is sensitive to changes in redox status and is notably susceptible to modifications of cysteine residues, such as oxidation, electrophilic reaction, and S-nitrosylation of sulfhydryls. In this review, we focus on TRP channels, which directly sense redox status, and discuss the biological significance of cysteine modifications and the consequences of this chemical reaction for physiological responses.

Keywords: Ca2+ signaling; S-nitrosylation; TRP channels; TRPA1; TRPC5; TRPV1; cysteine modification; oxidative stress.

Figure 1

Model for activation of TRPC5 by NO. Possible protein conformation changes and chemical reactions during activation of TRPC5 by NO. NO modify the free sulfhydryl group of Cys553 accessible from the cytoplasmic side to open the activation gate. The modified Cys553 can be further attacked nucleophilically by the free sulfhydryl group of Cys558 to form an intramolecular disulfide bond, which may stabilize the channel in activation states.

Figure 2

Conserved cysteine residues on the N-terminal side of putative pore-forming regions in TRPs. Alignment of various TRPs with the Cys553/Cys558-containing TRPC5 sequence.

Figure 3

Proposed model for TRPC5-mediated feedback cycle of receptor-activated Ca²⁺ and NO signaling in caveolae of endothelial cells. Stimulation of 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. GPCR: G protein-coupled receptor.

Figure 4

Structural model for TRPA1 protein. Four identical TRPA1 subunits are believed to be combined in the formation a functional channel. Each subunit spanning the plasma membrane six times (transmembrane domains S1–S6) has a long cytoplasmic N-terminal domain. Ovals indicate ankyrin repeats, while filled circles indicate cysteine residues identified as crucial sites for covalent modification of TRPA1 (Hinman et al., ; Macpherson et al., ; Trevisani et al., ; Bessac et al., ; Maher et al., ; Takahashi et al., ; Taylor-Clark et al., 2009).