Pore Dilation Occurs in TRPA1 but Not in TRPM8 Channels

Chen, Jun; Kim, Dong‐Hee; Bianchi, Bruce R.; Cavanaugh, Eric J.; Faltynek, Connie R.; Kym, Philip R.; Reilly, Regina M.

doi:10.1186/1744-8069-5-3

Cited by 101 publications

(105 citation statements)

References 26 publications

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“…Alternatively, a permeation pathway for large organic ions coupled to ligand-gated channel activity, similar to that of ionotropic purinergic P2X receptors (32)(33)(34), represents an attractive conduit to introduce charged therapeutics into cytoplasms of select neuronal populations. For example, the mustard oil receptor TRPA1 responds to allyl-isothiocyanate to mediate YO-PRO-1 transport (35,36). Moreover, anionic transmitters ATP or GABA can pass pores of pannexin or bestrophin, respectively, underlying nonvesicular release of autocrine or paracrine factors in synapses (37)(38)(39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

Activity-dependent targeting of TRPV1 with a pore-permeating capsaicin analog

Wang

Chuang³

et al. 2011

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

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The capsaicin receptor TRPV1 is the principal transduction channel for nociception. Excessive TRPV1 activation causes pathological pain. Ideal pain mangement requires selective inhibition of hyperactive pain-sensing neurons, but sparing normal nociception. We sought to determine whether it is possible to use activity-dependent TRPV1 agonists to identify nerves with excessive TRPV1 activity, as well as exploit the TRPV1 pore to deliver charged anesthetics for neuronal silencing. We synthesized a series of permanently charged capsaicinoids and found that one, cap-ET, efficaciously evoked TRPV1-dependent entry of Ca 2+ or the large cationic dye YO-PRO-1 comparably to capsaicin, but far smaller electrical currents. Cap-ETinduced YO-PRO-1 transport required permeation of both the agonist and the dye through the TRPV1 pore and could be enhanced by kinase activation or oxidative covalent modification. Moreover, cap-ET reduced capsaicin-induced currents by a voltage-dependent block of the pore. A low dose of cap-ET elicited entry of permanently charged Na + channel blockers to effectively suppress Na + currents in sensory neurons presensitized with oxidative chemicals. These results implicate therapeutic potential of these unique TRPV1 agonists exhibiting activity-dependent ion transport but of minimal pain-producing risks.activity-dependent capsaicinoids | hyperalgesia | ion permeation | selective analgesia C apsaicin, a small lipophilic molecule from hot chili peppers, acts on sensory neurons by opening the TRPV1 channel. TRPV1 is activated by noxious temperatures (>43°C) and serves as an integrator for major pain-producing signals (1, 2). Inflammatory hyperalgesia is dramatically reduced in mice lacking TRPV1 (3, 4). Besides being an attractive target for pain management, TRPV1 regulates autonomic function, such as body temperature, blood vessel tone, and release of transmitters from sensory nerves (5-9). TRPV1 activated by capsaicin at a concentration far below the pain-producing threshold triggers neuropeptide release (7) and production of other second messengers (10). In light of the complexity of TRPV1 actions in physiology, one major challenge in developing TRPV1-based pain treatment is to target therapeutic compounds to selectively inhibit hyperactive nociceptive neurons while sparing nerves of normal thresholds for pain detection.Capsaicin is among the most powerful chemical agonists of TRPV1. Being small and hydrophobic, capsaicin crosses the plasma membrane readily to reach its intracellular ligand-binding site on TRPV1 (11, 12), leading to channel activation and cation permeation. TRPV1 activation rapidly depolarizes nerves to evoke acute pain sensation and allows Ca 2+ entry to initiate downstream signaling events such as neuropeptide release or production of other second messengers. Nevertheless, TRPV1 activation facilitates cellular transport of organic cations such as tetraethylammonium (TEA), N-methylglucamine (NMG) (13), and the quaternary ammonium Na + channel blocker QX-314 (14) or even larger fluor...

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Section: Discussionmentioning

confidence: 99%

Activity-dependent targeting of TRPV1 with a pore-permeating capsaicin analog

Wang

Chuang³

et al. 2011

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

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“…Recent evidence suggests that TRPA1 undergoes dynamic pore dilation during sustained agonist application, resulting in a transformation of the initially strong outward rectification toward an almost linear I/V shape (Chen et al, 2009;Banke et al, 2010). It may thus be possible that binding of apomorphine to TRPA1 either causes a rapid transition to a fully dilated pore or directly forces TRPA1 to adapt a conformation that is associated with a dilated permeation pathway.…”

Section: Discussionmentioning

confidence: 99%

Apomorphine Is a Bimodal Modulator of TRPA1 Channels

et al. 2012

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Apomorphine is a non-narcotic derivative of morphine, which acts as a dopamine agonist and is clinically used to treat "offstates" in patients suffering from Parkinson's disease. Adverse effects of apomorphine treatment include severe emesis and nausea, and ulceration and pain at the injection site. We wanted to test whether sensory transient receptor potential (TRP) channels are a molecular target for apomorphine. Here, we show that rTRPV1, rTRPV2, rTRPV3, and mTRPV4, as well as hTRPM8, and rTRPM3, which are expressed in dorsal root ganglion neurons, are insensitive toward apomorphine treatment. This also applied to the cellular redox sensor hTRPM2. On the contrary, human TRPA1 could be concentrationdependently modulated by apomorphine. Whereas the addition of apomorphine in the low micromolar range produced an irreversible activation of the channel, application of higher concentrations caused a reversible voltage-dependent inhibition of heterologously expressed TRPA1 channels, resulting from a reduction of single-channel open times. In addition, we provide evidence that apomorphine also acts on endogenous TRPA1 in cultured dorsal root ganglion neurons from rats and in the enterochromaffin model cell line QGP-1, from which serotonin is released upon activation of TRPA1. Our study shows that human TRPA1 is a target for apomorphine, suggesting that an activation of TRPA1 might contribute to adverse side effects such as nausea and painful injections, which can occur during treatment with apomorphine.

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“…TRPA1 pore dilation eventually allowed for permeation of large cationic molecules like Yo-Pro (376 Da; fluorescent probe), N-methyl-D-glucamine (195.2 Da) or the lidocaine derivative QX314 (363Da) [50] [51]. Probe permeation was reversed by TRPA1 antagonists like ruthenium red (RuR) and HC-030031 and, regardless of their reactive nature, pore dilation was observed both with electrophiles (AITC, cinnamaldehyde, 4-hydroxy nonenal) and non-electrophile compounds (farnesyl thiosalicylic acid and URB597).…”

Section: Biophysical Properties Of Trpa1mentioning

confidence: 99%

“…Whether 4-HNE plays a direct role in triggering pain in OA can only be speculated. Yet, the fact that TRPA1 can be detected in human synovial lining and that 4-HNE accumulates during oxidative stress to reach local concentrations (~5 mM) greatly exceeding its EC 50 at TRPA1 (~50 µM) would support the concept [100,108,109].…”

Section: Trpa1 Responds To a Variety Of Noxious Endogenous Reactive Cmentioning

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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Pore Dilation Occurs in TRPA1 but Not in TRPM8 Channels

Cited by 101 publications

References 26 publications

Activity-dependent targeting of TRPV1 with a pore-permeating capsaicin analog

Activity-dependent targeting of TRPV1 with a pore-permeating capsaicin analog

Apomorphine Is a Bimodal Modulator of TRPA1 Channels

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

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