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 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

New knowledge about the neural aspects of cough has revealed a complex network of pathways that initiate cough. The effect of inflammation on cough neural processing occurs at multiple peripheral and central sites within the nervous system. Evidence exists that direct or indirect neuroimmune interaction induces a complex response, which can be altered by mediators released by the sensory or parasympathetic neurons and vice versa. The aim of this study was to clarify changes of cough reflex sensitivity - the activity of airway afferent nerve endings - in asthmatic children.25 children with asthma and 15 controls were submitted to cough reflex sensitivity measurement - capsaicin aerosol in doubling concentrations (from 0.61 to 1250 µmol/l) was inhaled by a single breath method. Concentrations of capsaicin causing two (C2) and five coughs (C5) were reported. Asthmatic children' (11 boys and 14 girls, mean age 9 ± 1 yrs) cough reflex sensitivity (geometric mean, with the 95 % CI) for C2 was 4.25 (2.25-8.03) µmol/l vs. control C2 (6 boys and 9 girls, mean age 8 ± 1 yrs) was 10.61 (5.28-21.32) µmol/l (p=0.024). Asthmatic children' C5 was 100.27 (49.30-203.93) µmol/l vs. control C5 56.53 (19.69-162.35) µmol/l (p=0.348). There was a statistically significant decrease of C2 (cough threshold) in the asthmatic patients relative to controls (p-value for the two-sample t-test of log(C2) for the one-sided alternative, p-value = 0.024). The 95 % confidence interval for the difference of the mean C2 in asthma vs. control, [1.004, 6.207]. For C5, the difference was not statistically significant (p-value = 0.348). There was a statistically significant decrease of cough reflex sensitivity (the activity of airway afferent nerve endings) - C2 value in the asthmatic children relative to controls.

• MeSH
• Afferent Pathways drug effects   physiopathology   MeSH
• Asthma chemically induced   diagnosis   physiopathology   MeSH
• Child MeSH
• Capsaicin adverse effects   MeSH
• Cough chemically induced   diagnosis   physiopathology   MeSH
• Sensory System Agents adverse effects   MeSH
• Humans MeSH
• Prospective Studies MeSH
• Reflex drug effects   physiology   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Capsaicin MeSH
• Sensory System Agents MeSH

Itch is the most common chief complaint in patients visiting dermatology clinics and is analogous to cough and also sneeze of the lower and upper respiratory tract, all three of which are host actions trying to clear noxious stimuli. The pathomechanisms of these symptoms are not completely determined. The itch can originate from a variety of etiologies. Itch originates following the activation of peripheral sensory nerve endings following damage or exposure to inflammatory mediators. More than one sensory nerve subtype is thought to subservepruriceptive itch which includes both unmyelinated C-fibers and thinly myelinated Adelta nerve fibers. There are a lot of mediators capable of stimulating these afferent nerves leading to itch. Cough and itch pathways are mediated by small-diameter sensory fibers. These cough and itch sensory fibers release neuropeptides upon activation, which leads to inflammation of the nerves. The inflammation is involved in the development of chronic conditions of itch and cough. The aim of this review is to point out the role of sensory nerves in the pathogenesis of cough and itching. The common aspects of itch and cough could lead to new thoughts and perspectives in both fields.

• MeSH
• Histamine Agonists adverse effects   MeSH
• Histamine adverse effects   MeSH
• Capsaicin adverse effects   MeSH
• Cough chemically induced   physiopathology   MeSH
• Sensory System Agents adverse effects   MeSH
• Humans MeSH
• Nerve Fibers, Myelinated drug effects   physiology   MeSH
• Nerve Fibers, Unmyelinated drug effects   physiology   MeSH
• Sensory Receptor Cells drug effects   physiology   MeSH
• Neurons, Afferent drug effects   physiology   MeSH
• Peripheral Nerves drug effects   physiopathology   MeSH
• Pruritus chemically induced   physiopathology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Histamine Agonists MeSH
• Histamine MeSH
• Capsaicin MeSH
• Sensory System Agents MeSH

Our understanding of the general principles of the polymodal regulation of transient receptor potential (TRP) ion channels has grown impressively in recent years as a result of intense efforts in protein structure determination by cryo-electron microscopy. In particular, the high-resolution structures of various TRP channels captured in different conformations, a number of them determined in a membrane mimetic environment, have yielded valuable insights into their architecture, gating properties and the sites of their interactions with annular and regulatory lipids. The correct repertoire of these channels is, however, organized by supramolecular complexes that involve the localization of signaling proteins to sites of action, ensuring the specificity and speed of signal transduction events. As such, TRP ankyrin 1 (TRPA1), a major player involved in various pain conditions, localizes into cholesterol-rich sensory membrane microdomains, physically interacts with calmodulin, associates with the scaffolding A-kinase anchoring protein (AKAP) and forms functional complexes with the related TRPV1 channel. This perspective will contextualize the recent biochemical and functional studies with emerging structural data with the aim of enabling a more thorough interpretation of the results, which may ultimately help to understand the roles of TRPA1 under various physiological and pathophysiological pain conditions. We demonstrate that an alteration to the putative lipid-binding site containing a residue polymorphism associated with human asthma affects the cold sensitivity of TRPA1. Moreover, we present evidence that TRPA1 can interact with AKAP to prime the channel for opening. The structural bases underlying these interactions remain unclear and are definitely worth the attention of future studies.

• Keywords
• A-kinase anchoring protein, TRP channel, TRPA1, calmodulin, transient receptor potential,
• Publication type
• Journal Article MeSH

Exposure to repetitive low-frequency electromagnetic field (LF-EMF) shows promise as a non-invasive approach to treat various sensory and neurological disorders. Despite considerable progress in the development of modern stimulation devices, there is a limited understanding of the mechanisms underlying their biological effects and potential targets at the cellular level. A significant impact of electromagnetic field on voltage-gated calcium channels and downstream signalling pathways has been convincingly demonstrated in many distinct cell types. However, evidence for clear effects on primary sensory neurons that particularly may be responsible for the analgesic actions of LF-EMF is still lacking. Here, we used F11 cells derived from dorsal root ganglia neurons as an in vitro model of peripheral sensory neurons and three different protocols of high-induction magnetic stimulation to determine the effects on chemical responsiveness and spontaneous activity. We show that short-term (<180 sec.) exposure of F11 cells to LF-EMF reduces calcium transients in response to bradykinin, a potent pain-producing inflammatory agent formed at sites of injury. Moreover, we characterize an immediate and reversible potentiating effect of LF-EMF on neuronal spontaneous activity. Our results provide new evidence that electromagnetic field may directly modulate the activity of sensory neurons and highlight the potential of sensory neuron-derived cell line as a tool for studying the underlying mechanisms at the cellular and molecular level.

• Keywords
• bradykinin receptor, electromagnetic field, ion channel, primary sensory neuron, transient receptor potential channel,
• MeSH
• Bradykinin pharmacology   MeSH
• Cell Line MeSH
• Electromagnetic Fields * MeSH
• TRPA1 Cation Channel metabolism   MeSH
• Humans MeSH
• Sensory Receptor Cells drug effects   metabolism   MeSH
• Calcium metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Bradykinin MeSH
• TRPA1 Cation Channel MeSH
• TRPA1 protein, human MeSH Browser
• Calcium MeSH