The transient receptor potential ion channel TRPA1 is a Ca2+-permeable nonselective cation channel widely expressed in sensory neurons, but also in many nonneuronal tissues typically possessing barrier functions, such as the skin, joint synoviocytes, cornea, and the respiratory and intestinal tracts. Here, the primary role of TRPA1 is to detect potential danger stimuli that may threaten the tissue homeostasis and the health of the organism. The ability to directly recognize signals of different modalities, including chemical irritants, extreme temperatures, or osmotic changes resides in the characteristic properties of the ion channel protein complex. Recent advances in cryo-electron microscopy have provided an important framework for understanding the molecular basis of TRPA1 function and have suggested novel directions in the search for its pharmacological regulation. This chapter summarizes the current knowledge of human TRPA1 from a structural and functional perspective and discusses the complex allosteric mechanisms of activation and modulation that play important roles under physiological or pathophysiological conditions. In this context, major challenges for future research on TRPA1 are outlined.

• Keywords
• Chemosensation, Gating, Nociception, Sensory transduction, TRPA1 channel, Thermosensation,
• MeSH
• Allosteric Regulation MeSH
• Cryoelectron Microscopy methods   MeSH
• Transient Receptor Potential Channels metabolism   chemistry   physiology   MeSH
• TRPA1 Cation Channel * metabolism   chemistry   physiology   MeSH
• Humans MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Transient Receptor Potential Channels MeSH
• TRPA1 Cation Channel * MeSH
• TRPA1 protein, human MeSH Browser

The discovery of the role of the transient receptor potential ankyrin 1 (TRPA1) channel as a polymodal detector of cold and pain-producing stimuli almost two decades ago catalyzed the consequent identification of various vertebrate and invertebrate orthologues. In different species, the role of TRPA1 has been implicated in numerous physiological functions, indicating that the molecular structure of the channel exhibits evolutionary flexibility. Until very recently, information about the critical elements of the temperature-sensing molecular machinery of thermosensitive ion channels such as TRPA1 had lagged far behind information obtained from mutational and functional analysis. Current developments in single-particle cryo-electron microscopy are revealing precisely how the thermosensitive channels operate, how they might be targeted with drugs, and at which sites they can be critically regulated by membrane lipids. This means that it is now possible to resolve a huge number of very important pharmacological, biophysical and physiological questions in a way we have never had before. In this review, we aim at providing some of the recent knowledge on the molecular mechanisms underlying the temperature sensitivity of TRPA1. We also demonstrate how the search for differences in temperature and chemical sensitivity between human and mouse TRPA1 orthologues can be a useful approach to identifying important domains with a key role in channel activation.

• MeSH
• Ankyrins genetics   physiology   MeSH
• TRPA1 Cation Channel genetics   physiology   MeSH
• Humans MeSH
• Mice MeSH
• Cold Temperature MeSH
• Thermosensing genetics   physiology   MeSH
• Hot Temperature MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Ankyrins MeSH
• TRPA1 Cation Channel MeSH
• TRPA1 protein, human MeSH Browser

The Transient Receptor Potential Ankyrin 1 (TRPA1) channel is an integrative molecular sensor for detecting environmental irritant compounds, endogenous proalgesic and inflammatory agents, pressure, and temperature. Different post-translational modifications participate in the discrimination of the essential functions of TRPA1 in its physiological environment, but the underlying structural bases are poorly understood. Here, we explored the role of the cytosolic N-terminal residue Ser602 located near a functionally important allosteric coupling domain as a potential target of phosphorylation. The phosphomimetic mutation S602D completely abrogated channel activation, whereas the phosphonull mutations S602G and S602N produced a fully functional channel. Using mutagenesis, electrophysiology, and molecular simulations, we investigated the possible structural impact of a modification (mutation or phosphorylation) of Ser602 and found that this residue represents an important regulatory site through which the intracellular signaling cascades may act to reversibly restrict or "dampen" the conformational space of the TRPA1 channel and promote its transitions to the closed state.

• Keywords
• TRP channel, mutagenesis, phosphomimetic, phosphorylation, protein kinases, transient receptor potential ankyrin 1,
• MeSH
• Phosphorylation MeSH
• HEK293 Cells MeSH
• TRPA1 Cation Channel chemistry   genetics   metabolism   MeSH
• Protein Conformation MeSH
• Humans MeSH
• Models, Molecular MeSH
• Mutation * MeSH
• Protein Domains MeSH
• Serine metabolism   MeSH
• Molecular Dynamics Simulation MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• TRPA1 Cation Channel MeSH
• Serine MeSH
• TRPA1 protein, human MeSH Browser