Abstract
The transient receptor potential (TRP) cation channel superfamily comprises more than 50 channels that play crucial roles in physiological processes. TRP channels are responsive to several exogenous and endogenous biomolecules, with aldehydes emerging as a TRP channel trigger contributing to a cellular cascade that can lead to disease pathophysiology. The body is not only exposed to exogenous aldehydes via tobacco products or alcoholic beverages, but also to endogenous aldehydes triggered by lipid peroxidation. In response to lipid peroxidation from inflammation or organ injury, polyunsaturated fatty acids undergo lipid peroxidation to aldehydes, such as 4-hydroxynonenal. Reactive aldehydes activate TRP channels via aldehyde-induced protein adducts, leading to the release of pro-inflammatory mediators driving the pathophysiology caused by cellular injury, including inflammatory pain and organ reperfusion injury. Recent studies have outlined how aldehyde dehydrogenase 2 protects against aldehyde toxicity through the clearance of toxic aldehydes, indicating that targeting the endogenous aldehyde metabolism may represent a novel treatment strategy. An addition approach can involve targeting specific TRP channel regions to limit the triggering of a cellular cascade induced by aldehydes. In this review, we provide a comprehensive summary of aldehydes, TRP channels, and their interactions, as well as their role in pathological conditions and the different therapeutical treatment options.
Highlights
Exposure to endogenous and exogenous aldehydes has emerged as a key contributor to disease pathology in recent years [1,2]
Endogenous reactive aldehydes are produced by the lipid peroxidation of polyunsaturated fatty acids and induce the activation of transient receptor potential (TRP) channels by the covalent modification of specific intracellularly located amino acid residues, promoting conformational changes
The induction of channel opening by electrophilic aldehydes significantly differs from the binding of classic agonists, which use a lock-and-key binding mechanism, which shows that TRP channels play a key role in sensing oxidative stress beyond mediating nociception
Summary
Exposure to endogenous and exogenous aldehydes has emerged as a key contributor to disease pathology in recent years [1,2]. Evidence that aldehydes form adducts with TRP channels, leading to the activation of the cation channel and the subsequent calcium-induced release of pro-inflammatory mediators, has been accumulating [12]. Recent evidence demonstrates that reactive aldehydes themselves and through interaction with the TRP channel induce endothelial dysfunction in acute disease states, such as sepsis, and chronic disease states, such as diabetes [13,14,15,16,17]. This review focuses on the formation of endogenous aldehydes; their precise interaction with TRP cation channels—especially the TRPV1 and TRPA1 channels; and aims to dissect the possibilities for pharmacological strategies targeting their interface
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