The transient receptor potential channel TRPA1: from gene to pathophysiology

Abstract

The Transient Receptor Potential Ankyrin 1 channel (TRPA1), is a member of the large TRP family of ion channels, and functions as a Ca(2+) permeable non-selective cation channel in many different cell processes, ranging from sensory to homeostatic tasks. TRPA1 is highly conserved across the animal kingdom. The only mammalian TRPA subfamily member, TRPA1, is widely expressed in neuronal (e.g. sensory dorsal root and trigeminal ganglia neurons)- and in non-neuronal cells (e.g. epithelial cells, hair cells). It exhibits 14-19 amino-(N-)terminal ankyrin repeats, an unusual structural feature. The TRPA1 channel is activated by noxious cold (<17 °C) as well as by a plethora of chemical compounds that includes not only electrophilic compounds and oxidants that can modify, in an alkylative or oxidative fashion, nucleophilic cysteine residues in the channel's N-terminus, but also compounds that do not covalently bind to the channel proteins (e.g. menthol, nifedipin). Based on localization and functional properties, TRPA1 is considered a key player in acute and chronic (neuropathic) pain and inflammation. Moreover, its role in the (patho)physiology of nearly all organ systems is anticipated, and will be discussed along with the potential of TRPA1 as a drug target for the management of various pathological conditions.

Autonomic dysreflexia during bowel evacuation procedures and bladder filling in subjects with spinal cord injury

“…19 Axons of the sensory neurons from the thoracolumbar and lumbosacral dorsal root ganglia expressing TRPA1 (transient receptor potential ankyrin 1) are present in the pelvic nerves that reach the distal colon. 20 It is believed that TRPV1 neurons are involved in the regulation of colonic motor function, but usually not in nociception. 21 TRPA1 is necessary for normal mechanosensory function and the signaling of noxious mechanical stimuli.…”

Transient Receptor Potential Channel Opening Releases Endogenous Acetylcholine, which Contributes to Endothelium-Dependent Relaxation Induced by Mild Hypothermia in Spontaneously Hypertensive Rat but Not Wistar-Kyoto Rat Arteries

“…These observations suggest that the modulatory role of the nonneuronal cholinergic system on the response to cold may occur in more peripheral blood vessels. The observation that not only L-NAME but also TRAM-34 plus UCL 1684 inhibited the response in the mesenteric arteries implies that in these blood vessels endothelium-dependent hyperpolarization contributes to the response to cold (Earley et al, 2009;Nilius et al, 2012).…”

“…Activation of TRPM8 (Johnson et al, 2009), TRPA1 (Earley et al, 2009), or TRPV4 (Vincent andDuncton, 2012) leads to endothelium-dependent relaxations (Earley et al, 2009;Johnson et al, 2009). The relaxation caused by TRPA1 activation in rat cerebral arteries is mediated by activation of small and intermediate conductance calcium-activated potassium channels, and hence endothelium-dependent hyperpolarization (Earley et al, 2009;Nilius et al, 2012), while that by TRPV4 activation in mouse small mesenteric and rat carotid arteries involves both NO and endothelium-dependent hyperpolarization (Mendoza et al, 2010). Because these three subtypes of TRP channels can cause increased intracellular Ca 21 concentration and generation of endothelium-derived relaxing factors, they are likely candidates for producing endothelium-dependent responses to cooling.…”

Nerve Growth Factor and Nociception: From Experimental Embryology to New Analgesic Therapy

“…There is a highly controversial literature on the possible involvement of the mustard oil activated Trp channel TRPA1 in mechanotransduction (Patel et al, 2010;Nilius et al, 2012). The TRPA1 channel undoubtedly plays an important role governing the chemosensitivity of nociceptive afferents and is required for normal inflammatory pain behaviors in mice (Bautista et al, 2006;Kwan et al, 2006;Macpherson et al, 2007;McNamara et al, 2007).…”