Journal Club 2015.4.24

Pain-sensing TRPA1 channel resolved
nature14383

The TRPA1 ion channel activates pain pathways in response to noxious compounds. The structure of TRPA1 has now been solved, providing insight into how it functions.Pain-sensing TRPA1 channel resolved

Journal Club 2015.4.17

Structure of the TRPA1 ion channel suggests regulatory mechanisms

Candice E. Paulsen1*, Jean-Paul Armache2*, Yuan Gao1,2, Yifan Cheng2 & David Julius1

doi:10.1038/nature14367 nature14367

The TRPA1 ion channel (also known as the wasabi receptor) is a detector of noxious chemical agents encountered in our environment or produced endogenously during tissue injury or drug metabolism. These include a broad class of electrophiles that activate the channel through covalent protein modification. TRPA1 antagonists hold potential for treating neurogenic inflammatory conditions provoked or exacerbated by irritant exposure. Despite compelling reasons to understand TRPA1 function, structural mechanisms underlying channel regulation remain obscure. Here we use single-particle electron cryo- microscopy to determine the structure of full-length human TRPA1 to 4 A ̊ resolution in the presence of pharmacophores, including a potent antagonist. Several unexpected features are revealed, including an extensive coiled-coil assembly domain stabilized by polyphosphate co-factors and a highly integrated nexus that converges on an unpredicted transient receptor potential (TRP)-like allosteric domain. These findings provide new insights into the mechanisms of TRPA1 regulation, and establish a blueprint for structure-based design of analgesic and anti-inflammatory agents.

Journal Club 2015.4.10

Antipruritic effect of cold stimulation at the Quchi Acupoint (LI11) in Mice

Kao-Sung Tsai123, Yung-Hsiang Chen12, Huey-Yi Chen12, Ein-Yiao Shen12, Yu-Chen Lee12, Jui-Lung Shen45, San-Yuan Wu1, Jaung-Geng Lin12, Yi-Hung Chen1* and Wen-Chi Chen12*

Abstract

Background

Acupuncture and moxibustion are used to treat pruritus and atopic dermatitis. However, whether cold stimulation (defined as that the temperature conducted under skin temperature) of acupoints affects itching in experimental murine models remains unclear.

Methods

The present study was designed to determine the therapeutic effects of different thermal stimulations at the Quchi acupoint (LI11) in a murine model in which scratching behaviour was elicited by subcutaneous injection with a pruritogenic agent (compound 48/80). Male ICR mice were divided into several groups as follows: control (saline), those receiving compound 48/80 and compound 48/80 with various thermal stimulations (5°C–45°C) at LI11 (n = 6 per group). The scratch response of each animal to these stimulations was recorded for 30 min. The antipruritic effect of the acupoint was further evaluated in LI11 and sham (non-acupoint) groups (n = 6 per group).

Results

Treatment with lower temperature (20°C) at the LI11 acupoint significantly attenuated compound 48/80-induced scratching; however, this antipruritic effect was not observed with stimulation at the sham point. The expression of c-fos in the neuron of the cervical spine induced by compound 48/80 was suppressed by cold stimulation at LI11. The antipruritic effect of cold stimulation was blocked by ruthium red (RR), a non-selective transient receptor potential (TRP) channel blocker, suggesting that TRP channels may play an important role in the antipruritic effect of cold stimulation at LI11 in mice.

Conclusions

This study demonstrated that cold stimulation at LI11 attenuated compound 48/80-induced scratching behaviour in mice, possibly by a TRP-related pathway.

Journal Club 2015.4.3

4200
Filename : 4200.pdf (619 KB)
Caption :

Gender Differences in Itch and Pain-related Sensations Provoked by Histamine, Cowhage and Capsaicin

Abstract:

Cowhage, capsaicin and histamine, all applied via spicules, were used to induce itch and pain-related sensations in 15 male and 15 female subjects. Sensory qualities were assessed by questionnaire; intensities and time courses of the “itching” and “burning” sensation were measured alternately, but continuously on a VAS. In addition, axon reflexes were assessed. Only histamine and capsaicin produced a clear axon reflex flare (histamine > capsaicin, male = female). The 3 types of spicules caused mixed burning and itching sensations with different time courses. In the beginning burning prevailed, in the following minutes histamine induced mostly itching, capsaicin predominantly burning, cowhage both sensory components equally. Female subjects experienced more pain-related sensations (questionnaire), and their ratings leaned more toward burning than those of males. These findings indicate that the mixed itching and burning sensations are differentially processed by both genders. No indications were found for gender specific differential processing in the primary afferents as reflected by nearly identical flare responses.

Authors:

Elisabeth M. Hartmann, Herman O. Handwerker, Clemens Forster

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