Oxidative challenges sensitize the capsaicin receptor by covalent cysteine modification

Chuang, Huai-hu; Lin, Stephanie

doi:10.1073/pnas.0902675106

Cited by 167 publications

(137 citation statements)

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“…The low efficacy of cap-ET to induce currents persisted even for TRPV1 maximally sensitized by phenylarsine oxide (PAO), a cysteine-reacting chemical mimicking cellular oxidative stress (I cap-ET /I cap = 3.0 ± 0.9% at −60 mV, n = 6, after a 5-min PAO sensitization, Fig. 1D) (20). Slow activation kinetics of cationic capsaicin analogs in Ca 2+ imaging is, therefore, not a trivial outcome of reduced potency or efficacy of charged capsaicinoids, but more likely a consequence of delayed access of these agonists to their intracellular ligand binding sites.…”

Section: Resultsmentioning

confidence: 99%

“…An agonist with the potential to stimulate activity-dependent therapeutic molecule transport will be most useful if it also exhibits a parallel increase of potency or efficacy for sensitized versus normal TRPV1. Protein kinase C activation (23)(24)(25)(26) and oxidative modification (20,27,28) are major biochemical pathways that enhance TRPV1 sensitivity to chemical agonists. PDBu and PAO, chemical activators stimulating PKC or mimicking cellular oxidation, respectively, could elicit TRPV1-dependent intracellular Ca 2+ rise (20,29).…”

Section: Resultsmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

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 authors thank Huai-hu Chuang for sharing a TRPV1 chimera cDNA clone (31) and Charles Bowman and Fred Sachs for reading the manuscript. This work was supported by grants from the National Institutes of Health (R01-GM65994/84891) and the National Science Foundation of China (31028006).…”

Section: Methodsmentioning

confidence: 99%

Modular thermal sensors in temperature-gated transient receptor potential (TRP) channels

Yao

Liu

Feng

2011

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

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The molecular basis of the thermal sensitivity of temperature-sensitive channels appears to arise from a specific protein domain rather than integration of global thermal effects. Using systematic chimeric analysis, we show that the N-terminal region that connects ankyrin repeats to the first transmembrane segment is crucial for temperature sensing in heat-activated vanilloid receptor channels. Changing this region both transformed temperature-insensitive isoforms into temperature-sensitive channels and significantly perturbed temperature sensing in temperature-sensitive wild-type channels. Swapping other domains such as the transmembrane core, the C terminus, and the rest of the N terminus had little effect on the steepness of temperature dependence. Our results support that thermal transient receptor potential channels contain modular thermal sensors that confer the unprecedentedly strong temperature dependence to these channels. chimera | temperature gating | temperature jump | thermosensation | pain T he ability to sense temperature is vital to living organisms. In mammals, the neural input on ambient temperature results from specialized groups of neurons that project to the skin. The transducers involve ion channels known as transient receptor potential (TRP) channels (1, 2), which constitute an array of biological thermometers responsive over a broad temperature gradient from noxious cold to noxious hot (3).The molecular mechanism by which temperature changes induce channel opening is not yet known, but the phenomenological tools to analyze the system are known from classical thermodynamic theory. The probability of channel opening follows a Boltzmann relationship to temperature. The enthalpy change (ΔH) between closed and open determines the slope sensitivity of the curve, whereas the entropy change (ΔS) affects its midpoint (T 1∕2 ). The term "threshold" is also commonly used in studies of temperature-sensitive channels to represent the change in temperature required for the response to be larger than the noise level of the recording. Changes in threshold could occur by changes in ∆H or T 1∕2 or the recording noise level.Thermodynamic analyses reveal that thermal TRP channels undergo large enthalpy changes, which accounts for their high temperature sensitivity (4-8). The opening of TRPV1, for example, involves an activation enthalpy of approximately 100 kcal/mol (7), five times the enthalpy change for ligand-or voltage-dependent gating [Q 10 ∼ 2-3 (ref. 9), equivalent to an enthalpy of approximately 20 kcal/mol]. If the free energy change were determined by enthalpy alone, the rate of gating would be very slow because the barrier would be too high. However, thermal TRP channels have evolved to have tightly coupled enthalpy and entropy changes so that the free energy change is relatively small (7). The threshold of activation summarizes the influence of all the temperature-insensitive processes that can regulate gating including the membrane potential (5, 6, 10) and any other allosteric sources such as li...

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“…TRPV1 is subject to extensive modulation by neurotransmitters, inflammatory cytokines, growth factors, local hormones, and oxidative chemicals, thereby serving as an integration device for processing nociceptive information (2)(3)(4)(5)(6)(7)(8). As a substrate of many cellular signaling pathways, TRPV1 employs distinct cytoplasmic domains to translate various modulatory inputs into channel openings or closures, which ultimately adjust excitability of sensory afferents.…”

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confidence: 99%

“…Oxidation is one of the most robust stimulators of TRPV1 activity (2,9). It is conserved in both mammalian and avian TRPV1s, although birds and mammals have diverged during evolution to become differentially sensitive to capsaicin, the principal mammalian deterrent in chili peppers, and other endogenous lipid agonists (10).…”

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confidence: 99%

C-terminal Dimerization Activates the Nociceptive Transduction Channel Transient Receptor Potential Vanilloid 1

Wang

Chuang

2011

Journal of Biological Chemistry

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Background: Oxidation sensitizes nociception by covalent cysteine modification of pain transduction transient receptor potential vanilloid 1 (TRPV1) channels. Results: Cysteines within a unique C-terminal region are ligated to form intersubunit disulfide bonds to sensitize TRPV1. Conclusion: Dimerization of adjacent C termini activates TRPV1. Significance: This is potentially the first example of channel activation by physical approximation of two intrinsically unstructured peptide linkers.

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Oxidative challenges sensitize the capsaicin receptor by covalent cysteine modification

Cited by 167 publications

References 56 publications

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

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

Modular thermal sensors in temperature-gated transient receptor potential (TRP) channels

C-terminal Dimerization Activates the Nociceptive Transduction Channel Transient Receptor Potential Vanilloid 1

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