Species Comparison and Pharmacological Characterization of Human, Monkey, Rat, and Mouse TRPA1 Channels

Bianchi, Bruce R.; Zhang, Xufeng; Reilly, Regina M.; Kym, Philip R.; Yao, Betty B.; Chen, Jun

doi:10.1124/jpet.111.189902

Cited by 65 publications

(58 citation statements)

References 31 publications

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“…Mutational and chimeric strategies have been used to suggest specific thermosensitive regions and drug binding sites in TRP channels (8, 11, 13, 14, 16, 17, 19, 40). In this study, using the purified N-terminal ARD-deleted hTRPA1 to avoid potential artifacts in TRPA1 function caused by mutations or the creation of xenogeneic channels (7), we clearly show that the cold sensitivity and the binding site for HC030031, an inhibitor of rodent TRPA1 and hTRPA1 (7,41), are located outside the N-terminal ARD. The search for a specific cold-sensitive region in mammalian TRPA1 channels should, thus, be directed toward the transmembrane and the C-terminal domains of TRPA1.…”

Section: Discussionmentioning

confidence: 84%

Human TRPA1 is intrinsically cold- and chemosensitive with and without its N-terminal ankyrin repeat domain

Moparthi

Survery

Kreir

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

137

162

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We have purified and reconstituted human transient receptor potential (TRP) subtype A1 (hTRPA1) into lipid bilayers and recorded single-channel currents to understand its inherent thermo-and chemosensory properties as well as the role of the ankyrin repeat domain (ARD) of the N terminus in channel behavior. We report that hTRPA1 with and without its N-terminal ARD (Δ1-688 hTRPA1) is intrinsically cold-sensitive, and thus, cold-sensing properties of hTRPA1 reside outside the N-terminal ARD. We show activation of hTRPA1 by the thiol oxidant 2-((biotinoyl)amino)ethyl methanethiosulfonate (MTSEA-biotin) and that electrophilic compounds activate hTRPA1 in the presence and absence of the N-terminal ARD. The nonelectrophilic compounds menthol and the cannabinoid Δ 9 -tetrahydrocannabiorcol (C16) directly activate hTRPA1 at different sites independent of the N-terminal ARD. The TRPA1 antagonist HC030031 inhibited cold and chemical activation of hTRPA1 and Δ1-688 hTRPA1, supporting a direct interaction with hTRPA1 outside the N-terminal ARD. These findings show that hTRPA1 is an intrinsically cold-and chemosensitive ion channel. Thus, second messengers, including Ca 2+ , or accessory proteins are not needed for hTRPA1 responses to cold or chemical activators. We suggest that conformational changes outside the N-terminal ARD by cold, electrophiles, and nonelectrophiles are important in hTRPA1 channel gating and that targeting chemical interaction sites outside the N-terminal ARD provides possibilities to fine tune TRPA1-based drug therapies (e.g., for treatment of pain associated with cold hypersensitivity and cardiovascular disease).cold sensing | irritants | pain | sensory neuron | TRP channels A number of vertebrate and invertebrate transient receptor potential (TRP) ion channels have been implicated in temperature sensation (1-3), but only the rat menthol receptor TRP subtype M8 (TRPM8) and the rat capsaicin receptor TRP subtype V1 (TRPV1) have been shown to possess intrinsic thermosensitivity (4, 5). In 2003, Story et al. (6) proposed that the mouse TRPA1 is a noxious cold sensor. Story et al. (6) showed that TRPA1 was present in nociceptive primary sensory neurons and that CHO cells heterologously expressing the mouse TRPA1 displayed cold sensitivity. Most subsequent studies of cold responses in heterologous TRPA1 expression systems, isolated primary sensory neurons, and whole animals have provided evidence in support of mouse and rat TRPA1 being involved in noxious cold transduction (7). Interestingly, a familial episodic pain syndrome triggered by cold is caused by a gain-of-function mutation in the TRPA1 gene, indicating that TRPA1 may have a key role in human noxious cold sensation (8). Thus, human TRPA1 (hTRPA1) may be a relevant drug target for treatment of this condition and other pathological conditions, such as inflammation, nerve injury, and chemotherapy-induced neuropathy, that are characterized by TRPA1-dependent cold allodynia or hypersensitivity (7). However, in vitro studies of the expressed hTRPA1 h...

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Section: Discussionmentioning

confidence: 84%

Human TRPA1 is intrinsically cold- and chemosensitive with and without its N-terminal ankyrin repeat domain

Moparthi

Survery

Kreir

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

137

162

View full text Add to dashboard Cite

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“…It is noteworthy that menthol induces cold allodynia in healthy volunteers, while producing analgesic effects in patients with neuropathic pain (Wasner et al, 2008). TRPM8 and TRPA1 have been identified as the cold-and menthol-sensitive channels (McKemy et al, 2002;Peier et al, 2002;Karashima et al, 2007;Bianchi et al, 2012). The peripheral mechanism of menthol-induced cold hyperalgesia is thought to be induced by activating TRPM8 and TRPA1 channels (Gentry et al, 2010;Knowlton et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Central Mechanisms of Menthol-Induced Analgesia

Rong

Tian

Gao

et al. 2012

J Pharmacol Exp Ther

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Menthol is one of the most commonly used chemicals in our daily life, not only because of its fresh flavor and cooling feeling but also because of its medical benefit. Previous studies have suggested that menthol produces analgesic action in acute and neuropathic pain through peripheral mechanisms. However, the central actions and mechanisms of menthol remain unclear. Here, we report that menthol has direct effects on the spinal cord. Menthol decreased both ipsilateral and contralateral pain hypersensitivity induced by complete Freund's adjuvant in a dose-dependent manner. Menthol also reduced both first and second phases of formalin-induced spontaneous nocifensive behavior. We then identified the potential central mechanisms underlying the analgesic effect of menthol. In cultured dorsal horn neurons, menthol induced inward and outward currents in a dose-dependent manner. The menthol-activated current was mediated by Cl Ϫ and blocked by bicuculline, suggesting that menthol activates ␥-aminobutyric acid type A receptors. In addition, menthol blocked voltage-gated sodium channels and voltage-gated calcium channels in a voltage-, state-, and usedependent manner. Furthermore, menthol reduced repetitive firing and action potential amplitude, decreased neuronal excitability, and blocked spontaneous synaptic transmission of cultured superficial dorsal horn neurons. Liquid chromatography/tandem mass spectrometry analysis of brain menthol levels indicated that menthol was rapidly concentrated in the brain when administered systemically. Our results indicate that menthol produces its central analgesic action on inflammatory pain probably via the blockage of voltage-gated Na ϩ and Ca 2ϩ channels. These data provide molecular and cellular mechanisms by which menthol decreases neuronal excitability, therefore contributing to menthol-induced central analgesia.

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“…Analogous discrepancies have been seen for non-reactive ligands like caffeine and menthol [39,40]. The in vitro pharmacology (potency and type of effect) of caffeine, menthol and CMP1 on TRPA1 were similar between rhesus monkey and human channels (sharing 96.9% a.a. identity) but neatly distinct between human and rat or mouse channels (nonetheless sharing 96.6% a.a. identity) indicating that, rather than rat or mice, rhesus monkey may be a good surrogate species to human in preclinical studies [41]. Residues in the distal N-terminus between amino acid 231 and 287 are critical to explain the shift of some ligands from antagonist to agonist.…”

Section: Cross-species Differences and Relevance To Trpa1 Drug Discoverymentioning

confidence: 99%

Roles of TRPA1 in Pain Pathophysiology and Implications for the Development of a New Class of Analgesic Drugs

Radresa¹,

Dahllöf²,

Nyman³

et al. 2013

TOPAINJ

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Abstract:The Transient Receptor Potential A1 (TRPA1) ion channel has evolved in animals to respond to signals from a variety of sensory stimuli. Many structural determinants of its multimodal activation have been identified to date. TRPA1 activities include responses to exogenous chemical irritants, responses to endogenous inflammatory mediators, zinc, voltage, temperature or stretch and subtle yet critical modulation by calcium ions. TRPA1 has emerged as an important target for several types of pain and inflammatory conditions because of its limited expression profile and its demonstrated roles in mediating different types of pain and sensitization of peripheral sensory afferents. Despite observed species differences in channel pharmacology, recent genetic evidence in human brings some hope that preclinical efficacy in disease models will translate to patient condition. During the past decade, various groups have investigated the development of a new class of analgesic drugs or anti-tussive agents aimed at blocking TRPA1 activity in primary sensory afferents. Several companies are advancing toward clinical proof of concept studies. This review aims to summarize key advances in the understanding of TRPA1 with regard to its roles and implications for patient conditions.

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Species Comparison and Pharmacological Characterization of Human, Monkey, Rat, and Mouse TRPA1 Channels

Cited by 65 publications

References 31 publications

Human TRPA1 is intrinsically cold- and chemosensitive with and without its N-terminal ankyrin repeat domain

Human TRPA1 is intrinsically cold- and chemosensitive with and without its N-terminal ankyrin repeat domain

Central Mechanisms of Menthol-Induced Analgesia

Roles of TRPA1 in Pain Pathophysiology and Implications for the Development of a New Class of Analgesic Drugs

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