XB-ART-57405J Tradit Complement Med September 1, 2020; 10 (5): 446-453.
Effect of 158 herbal remedies on human TRPV1 and the two-pore domain potassium channels KCNK2, 3 and 9.
Background and aim: Herbal medicines are used to treat a broad number of maladies. However, the pharmacological profile of most remedies is poorly understood. We investigated the effect of herbal remedies from kampo, traditional Chinese medicine (TCM) and other phytotherapies on human two-pore domain potassium channels (KCNK channels; TREK-1, TASK-1 and TASK-3) as well as the human TRPV1 channel. KCNK channels are responsible for the background potassium current of excitable cells, thus essential for the maintenance of the resting membrane potential. Hence, modulators of KCNK channels are of medical significance, e.g. for the treatment of sleep disorders and pain. The transient receptor potential channel TRPV1 is a pain detector for noxious heat. Agonists of this receptor are still used for the treatment of pain in ectopic applications. Experimental procedure: We evaluated the effect of 158 herbal remedies on these channels in a heterologous expression system (Xenopus laevis oocytes) using the two-electrode voltage-clamp technique with the aim of increasing the comprehension of their pharmacological profile. Results and conclusion: Some remedies with modulating effects were identified such as Angelica pubescens (radix), which inhibit TASK-1 and TASK-3 channels. Furthermore, the modulatory effects of the most effective remedies on the two TASK family members TASK-1 and TASK-3 correlate positively, reflecting their close relation. For the TRPV1 channel Terminalia chebula and Alchemilla xanthochlora were identified as potentiators. This study identifies a variety of herbal remedies as modulators of human K2P and TRPV1 channels and gives new insights into the pharmacological profile of these herbal remedies.
PubMed ID: 32953560
PMC ID: PMC7484967
Article link: J Tradit Complement Med
Genes referenced: dtl kcnk2 trpv1
Article Images: [+] show captions
|Fig. 1. Exemplary recordings with the ramp series protocol for ethanol (A), the control application of piperine (B) and the negative modulation by Magnolia officinalis (cortex) on TASK-1 (C) as well as Angelica pubescens (radix) on TASK-3 (D). Recordings were done with a voltage ramp series protocol (ramp duration = 700 ms, voltage range: 100 to 50 mV). Applications are indicated by the application bars above the trace. Ethanol (0.5 vol.-%) exerts no effect (A). The control application of piperine (100 μM) caused a reversible inhibition of the currents. The applications of the tinctures (0.1 vol.-%) reversibly inhibits TASK-1 (C) and TASK-3 (D) currents.|
|Fig. 2. Best eight negative and positive KCNK channel modulators of 158 herbal remedies for TREK-1 (A), TASK-1 (B) and TASK-3 (C). KCNK channel modulation is calculated as the ratio of the current amplitudes during and prior to the application of the tincture (modulation = Iapplication/Ireference). Data are shown as mean ± SEM (n = 3–9 (A), n = 3–13 (B), n = 3–12 (C) ∗: p < 0.05; ∗∗: p < 0.005; Student’s t-test (Bonferroni corrected)).|
|Fig. 3. Screening reflects close relation of the TASK family members TASK-1 and TASK-3. To test the hypothesis of relation dependent coincidences in our screening between the two TASK family members TASK-1 and TASK-3, we correlated the effect of the best eight modulators shown in Fig. 2 for all three channel combinations. Linear regression was performed and the Pearson correlation coefficient (PCC) as well as the significance of this correlation (p-value) are shown in each panel. Moreover, sequence similarity of each channel combination is depicted. A) Screening results of TASK-1 and TASK-3 channels possess a significant positive correlation and 74.5% sequence identity (n = 24). B, C) Neither the combination of TASK-1 nor that of TASK-3 with TREK-1 shows a correlation of the strongest modulatory effects (n = 29). Furthermore, sequence identity is low for this combinations (TASK-1 vs. TREK-1 = 30.5%, TASK-3 vs. TREK-1 = 29.9%).|
|Fig. 4. Strongest ten direct activating remedies for the TRPV1 channel. Direct activating effects were normalized to the amplitude of capsaicin-induced currents (10 μM capsaicin). Data are shown as mean ± SEM. None of the remedies possesses direct activating effects different from NFR application, which mimics the process of application mechanically (ns: p > 0.05; Student’s t-test (Bonferroni corrected), n = 3–5).|
References [+] :
Alexeev, The natural products magnolol and honokiol are positive allosteric modulators of both synaptic and extra-synaptic GABA(A) receptors. 2012, Pubmed