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Transient Receptor Potential Channels and Itch
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Mahar Fatima, Jingyi Liu, Bo Duan
TRPA1 (also known as ANKTM1) is the only member of the TRPA subfamily in mammals. TRPA1 channels are characterized by the extensive ankyrin repeats array (16 in humans) (54–56). Ankyrin repeats are 33-amino-acid motifs that are predicted to mediate protein-protein interactions. TRPA1 is selectively expressed in a subset of small-diameter neurons in the dorsal root, trigeminal, and nodose ganglia and keratinocytes (57–60). TRPA1 can be activated by a range of inflammatory agents such as reactive carbonyl species, 4-hydroxynonenal (4-HNE) and 4-oxononenal (4-ONE), and reactive nitrogen species (ROS) (61). Prostaglandin derivative 15d-PGJ2 can exclusively activate TRPA1, but not TRPV1 or TRPM8 (62). Exogenous chemicals that can activate the TRPA1 channel include acrolein (found in tear gas), anesthetics such as isoflurane and lidocaine, allyl isothiocyanate (AITC) found in mustard, cinnamaldehyde (found in cinnamon), and allicin (found in garlic) (61). TRPA1 was initially suggested to contribute to noxious cold sensation (63), which is still controversial (64). Current evidence indicates that TRPA1 plays an important role in pain and itch. Itch-related G protein-coupled receptors (GPCRs), such as Mas-related G protein-coupled receptors A3 (MrgprA3) and MrgprC11, can positively regulate activation of TRPA1 channels. Genetic manipulation and pharmacological blockade studies have shown that TRPA1 functions as the downstream mediator of GPCR signaling in acute and chronic itch.
Pathophysiology of Detrusor Overactivity
Published in Jacques Corcos, Gilles Karsenty, Thomas Kessler, David Ginsberg, Essentials of the Adult Neurogenic Bladder, 2020
Sachin Malde, Jalesh N. Panicker
Spinal reflex pathways emerge following damage to the suprasacral spinal cord that trigger bladder overactivity. Afferent nerves conveying sensations from the LUT to the spinal cord contain unmyelinated C-fibers that have a much greater threshold for activation and are therefore quiescent in health (Figure 2.3). Following SCI, C-fibers become sensitized and are mechanosensitive at lower bladder volumes.1 It has been shown in experimental animal models of SCI that a C-fiber afferent mediated segmental spinal reflex emerges, resulting in involuntary detrusor contractions at low bladder volumes (Figure 2.2).32,33 The density of expression of capsaicin-sensitive TRPV1 receptors and P2X3 is increased in suburothelial nerves and basal layers of the urothelium and is thought to play a critical role in the pathogenesis of DO following SCI.34 Clinical trials have shown the efficacy of capsaicin35 and its ultrapotent analog resiniferatoxin36 in managing DO. Upregulation of TRPA1 protein and mRNA levels has also been demonstrated in rat SCI models.37
Basic Thermal Physiology: What Processes Lead to the Temperature Distribution on the Skin Surface
Published in Kurt Ammer, Francis Ring, The Thermal Human Body, 2019
TRPA1 was localized in the peripheral nervous system and in the hair cells of the inner ear. A temperature less than 17°C activates the transient receptor potential thermally, cinnamaldehyde, main compound of cinnamon essential oil, mustard oil, allicin and icilin lead also to the activation of TRPA1.
Neuronal and non-neuronal TRPA1 as therapeutic targets for pain and headache relief
Published in Temperature, 2023
Luigi F. Iannone, Romina Nassini, Riccardo Patacchini, Pierangelo Geppetti, Francesco De Logu
TRPA1 is co-expressed and localized with other TRP channels (i.e. TRPV1 and TRPV4) [13] in a subset of primary sensory neurons of the trigeminal (TG), vagal (VG), and dorsal root ganglia (DRG), particularly in thinly myelinated Aδ fibers and unmyelinated C fibers [17]. TRPA1 has also been detected in the central nervous system (CNS) (e.g. cortex, caudate nucleus, amygdala, and hypothalamus) where its role is still unknown [18]. Although TRPA1 is found in non-peptidergic neurons as it co-localized with the purinergic P2X3 receptor, isolectin B4, or the Na1.8 channel [19,20], it is worth noting that at least a quarter of neurons expressing TRPA1 are peptidergic Aδ- and C-fiber nociceptors, which release the proinflammatory neuropeptides, substance P (SP), neurokinin A (NKA), and calcitonin gene-related peptide (CGRP), from their peripheral and central endings [19]. The peripheral release of neuropeptides elicits neurogenic inflammation, which consists mainly of plasma protein extravasation in post-capillary venules (mediated by SP) and dilation of arterioles (mediated by CGRP) [21–23]. Preclinical and recent clinical evidence support the critical role of CGRP, but not SP, in neurogenic inflammation in humans and migraine-related pain [24].
Effects of homocysteine and memantine on oxidative stress related TRP cation channels in in-vitro model of Alzheimer’s disease
Published in Journal of Receptors and Signal Transduction, 2021
İshak Suat Övey, Mustafa Nazıroğlu
Transient receptor potential (TRP) superfamily contains 28 channel protein members in mammalian. TRP ankyrin 1 (TRPA1) is single member of ankyrin subfamily, because of ankyrin repeats of the N-terminal region. TRPA1 is activated by different stimuli, including cinnamaldehyde (CIN) [7]. TRP Melastatin 2 (TRPM2) is second member of melastatin TRP subfamily, has unique Adenosine diphosphate ribose (ADPR) pyrophosphatase enzyme activity domain in the C-terminal Nudix motif. TRPM2 is separately activated by ADPR and NAD+ [8]. TRP vanilloid 1 (TRPV1) is also a member of vanilloid subfamily and it is activated by different chemical stimuli such as capsaicin (CAPSN), piperine and resiniferatoxin [9]. Results of recent studies indicated that the TRPA1, TRPM2 and TRPV1 in hippocampus are also activated by oxidative stress [10–12]. Brain areas such as hippocampus, temporal and frontal lobes have main roles in etiology of AD and expression levels of TRPA1, TRPM2 and TRPV1 are high in the areas [13–15]. However, involvements of the TRPA1, TRPM2 and TRPV1 in etiology of AD have not been clarified yet.
Investigational drugs in early phase clinical trials targeting thermotransient receptor potential (thermoTRP) channels
Published in Expert Opinion on Investigational Drugs, 2020
Asia Fernández-Carvajal, Rosario González-Muñiz, Gregorio Fernández-Ballester, Antonio Ferrer-Montiel
Human and animal data implicate TRPA1 in a variety of pain conditions and are thought to play a major role in the pathogenesis of several disease states. Gain-of-function mutations in the human gene cause a familial episodic pain syndrome, in which debilitating upper-body pain can be triggered by stressors [76]. In rodents, neuropathic injury increases neuronal expression of TRPA1 [77]. Furthermore, genetic deletion or pharmacological inhibition of TRPA1 reduces pain behaviors in inflammatory, visceral, and neuropathic pain states [78]. There is evidence linking TRPA1 to the cold allodynia that develops following chemotherapy [79]. In animals with experimental osteoarthritis, blocking pharmacologically TRPA1 attenuated mechanical hypersensitivity in nociceptive neurons of the spinal dorsal horn [80]. The TRPA1 antagonist HC-030031 attenuated bladder overactivity in models of cyclophosphamide-induced cystitis and spinal cord injury [81]. In respiratory disorders, TRPA1 expressed by lung fibroblasts might play a role in the pathogenesis of asthma and Chronic Obstructive Pulmonary Disease (COPD) [82]. Furthermore, TRPA1 has also been implicated in migraine, dental pain, and pain secondary to diabetic neuropathy [69].