Mammalian Transient Receptor Potential TRPA1 Channels: From Structure to Disease

Abstract

The transient receptor potential ankyrin (TRPA) channels are Ca2+-permeable nonselective cation channels remarkably conserved through the animal kingdom. Mammals have only one member, TRPA1, which is widely expressed in sensory neurons and in non-neuronal cells (such as epithelial cells and hair cells). TRPA1 owes its name to the presence of 14 ankyrin repeats located in the NH2 terminus of the channel, an unusual structural feature that may be relevant to its interactions with intracellular components. TRPA1 is primarily involved in the detection of an extremely wide variety of exogenous stimuli that may produce cellular damage. This includes a plethora of electrophilic compounds that interact with nucleophilic amino acid residues in the channel and many other chemically unrelated compounds whose only common feature seems to be their ability to partition in the plasma membrane. TRPA1 has been reported to be activated by cold, heat, and mechanical stimuli, and its function is modulated by multiple factors, including Ca2+, trace metals, pH, and reactive oxygen, nitrogen, and carbonyl species. TRPA1 is involved in acute and chronic pain as well as inflammation, plays key roles in the pathophysiology of nearly all organ systems, and is an attractive target for the treatment of related diseases. Here we review the current knowledge about the mammalian TRPA1 channel, linking its unique structure, widely tuned sensory properties, and complex regulation to its roles in multiple pathophysiological conditions.

Human TRPA1 is an inherently mechanosensitive bilayer-gated ion channel

“…The finding that mammalian TRPA1 is activated by more than hundred different chemical compounds including thiol-reactive electrophilic compounds and oxidants as well as nonelectrophilic compounds such as menthol and cannabinoids has consolidated TRPA1 as a unique chemosensor (5,6). The original discovery of TRPA1 as a noxious cold sensor has been much debated but gained a lot of support over time (5,6). Furthermore, TRPA1 has recently been revealed as an intrinsic warmth/heat receptor that may contribute to sensing warmth and uncomfortable heat in mammalians (5).…”

Calcium activates purified human TRPA1 with and without its N-terminal ankyrin repeat domain in the absence of calmodulin

“…The effect of calcium on TRPA1 is mechanistically intriguing, and encompasses channel activation by calcium alone as well as calcium channel sensitization/desensitization of ligand activation (5). These effects of calcium may occur by a direct interaction with TRPA1 or as a result of association with a calcium binding partner such as calmodulin (6)(7)(8)(9)(11)(12)(13)(14).…”

“…These effects of calcium may occur by a direct interaction with TRPA1 or as a result of association with a calcium binding partner such as calmodulin (6)(7)(8)(9)(11)(12)(13)(14). The site of action may be on the cytoplasmic N-and C-termini (5). In this, study, we have addressed the possibility of a direct interaction between calcium and purified hTRPA1 without any interplay with other calcium-sensitive proteins including calmodulin, TRPV1 and A-kinase anchoring protein (AKAP) that can associate with TRPA1 and influence its function (5,13).…”

“…The site of action may be on the cytoplasmic N-and C-termini (5). In this, study, we have addressed the possibility of a direct interaction between calcium and purified hTRPA1 without any interplay with other calcium-sensitive proteins including calmodulin, TRPV1 and A-kinase anchoring protein (AKAP) that can associate with TRPA1 and influence its function (5,13).…”

“…Importantly, TRPA1 was also shown to be activated by an increase in the intracellular free calcium concentration (2). Whereas electrophiles are believed to promote TRPA1 channel opening primarily by binding to cysteine residues within the cytoplasmic N-terminus, the mechanism by which calcium modulates TRPA1 activity is not obvious (4,5). Studies have shown a direct activation of TRPA1 by calcium in cell-membrane inside-out patches containing heterologously expressed TRPA1 (6)(7)(8).…”