Charles University-- Přemysl Mladěnka研究团队在Food & Function发表题目为“The quercetin metabolite 4-methylcatechol causes vasodilation via voltage-gated potassium (KV) channels”研究论文（槲皮素代谢物 4-甲基儿茶酚通过电压门控钾 (KV) 通道引起血管舒张）。摘要： 膳食多酚与许多有益的心血管作用有关。然而，这些作用更可能归因于肠道微生物群形成的小酚类代谢物，这些代谢物在体循环中达到足够的浓度。4-甲基儿茶酚 (4-MC) 就是这样一种代谢物。由于它被证明具有显著的血管舒张作用，本研究旨在揭示其作用机制。为此，我们采用了体外实验和计算机模拟方法。第一步，对大鼠主动脉环进行等长张力记录。4-MC 增强了环核苷酸的作用，但这种作用不是由可溶性鸟苷酸环化酶 (sGC)、环磷酸腺苷水平的改变或蛋白激酶 G 介导的。因此，考虑了钙或钾通道等下游靶点。抑制电压门控 K+ 通道 (KV) 会显著降低 4-MC 的作用，抑制 KV7 同工型会部分降低血管舒张。相反，其他类型的 K+ 通道或 L 型 Ca2+ 通道不参与。计算机反向对接证实 4-MC 通过氢键和疏水相互作用与 KV7.4 结合。具体来说，它与 KV7.4 激活的两个关键残基相互作用：Trp242 和 Phe246。总之，我们的研究结果表明 4-MC 通过打开 KV 通道发挥血管舒张作用，而 KV7.4 参与其中。研究结果：环状核苷酸途径Fig. 3 (A) Effect of 4-methylcatechol (4-MC, 15 μM) on relaxation induced by sodium nitroprusside. (B) Effect of 4-MC (15 μM) on relaxation induced by forskolin. (C) Concentration-dependent curves obtained with 4-MC in the presence and absence of the soluble guanylate cyclase inhibitor ODQ (1 μM). (D) Impact of inhibition of PKG-Iα,β isoforms by Rp-8-pCPT-cGMPS (1 μM) or DT-3 (1 μM) on 4-MC-induced vasorelaxation (70 μM, i.e., concentration able to induce ∼80% relaxation).BKCa、KATP、KIR 和 KV 通道Fig. 4 (A) Effect of inhibition of vascular potassium (K+) channels (BKCa, KATP, KIR and KV) on the vasodilatory activity of 4-methylcatechol (4-MC). Concentration-dependent curves for the vasorelaxation induced by 4-MC in the absence (controls) and presence of (A) iberiotoxin (20 nM), (B) glibenclamide (10 μM), (C) BaCl2 (50 μM), (D) 4-aminopyridine (3 mM), and (E) linopirdine (10 μM).L 型 Ca2+ 通道和 SERCAFig. 5 Effect of 4-methylcatechol (4-MC) on vessel tonus as a function of extracellular (A) and intracellular (B) calcium.分子对接和分子间相互作用Fig. 6 Docking pose of 4-methylcatechol (green), 4-methylcatechol-1-sulfate (yellow), 4-methylcatechol-2-sulfate (purple), and retigabine (turquoise) in the ligand binding domain of the human voltage-gated potassium channel: (A) KV7.1; (B) KV7.2; (C) KV7.4.Fig. 7 2D representation of molecular interactions between the reference ligand (ML277 for KV7.1 and retigabine for KV7.2; 7.4), 4-methylcatechol (MC), 4-methylcatechol-1-sulfate (4-MC-1-S), and 4-methylcatechol-2-sulfate (4-MC-2-S).原文链接：https://doi.org/10.1039/D3FO04672A
