A TR(I)P through TRPA1 mechanosensitivity.

Abstract

Transient Receptor Potential ion channels have been described as polymodal thermo-, chemo-, photo-, and mechano-sensors, being involved in transducing a wide variety of stimuli. Within the TRP superfamily, one member the ankyrin-rich channel TRPA1 is indisputably the most versatile sensor of noxious chemicals, thermal and mechanical stimuli. TRPA1 interacts with a plethora of structurally unrelated exogenous and endogenous chemical ligands. In particular, an exceptionally large group of non-electrophilic TRPA1 agonists that is characterized by a common feature, the ability to intercalate into cellular membranes, inducing mechanical alterations. Our analysis of the chemical structures and properties of different alkyl-substituted phenol derivatives suggests a correlation between the partition coefficient and the potency to activate the channel. Similarly, exogenous amphipathic bacterial endotoxins can activate TRPA1 in a non-canonical pathway induced by changes in the mechanical properties of the membrane. Furthermore, TRPA1 can directly interact with cholesterol, and lipid raft integrity is necessary for proper channel activation and targeting to the plasma membrane. Since cholesterol regulates membrane thickness and fluidity, as well as the organization of lipid rafts where TRPA1 is expressed, we evaluated the cellular effects of cholesterol-depleting chemicals such as statins. Concisely, we provide an overview of the current knowledge of TRPA1 channel activation as a result of changes in the membrane properties induced by amphipathic structural lipid components such as cholesterol, exogenous amphipathic bacterial endotoxins, membrane partitioning chemicals, and cholesterol-reducing drugs. Although it remains uncertain how exactly TRPA1 contributes to mechano-transduction, its mechanical sensitivity might arise from a fundamental mechanism in which channel activation by chemical and physical stimuli results not only from classical compound-receptor interaction, but also from their intrinsic mechanosensory properties.