Department of Anatomy, Physiology and Biophysics, Faculty of Biology, University of Bucharest, Romania.
J Pharmacol Sci. 2010;114(3):332-40. doi: 10.1254/jphs.10172fp.
Linopirdine is a well known blocker of voltage-gated potassium channels from the Kv7 (or KCNQ) family that generate the so called M current in mammalian neurons. Kv7 subunits are also expressed in pain-sensing neurons in dorsal root ganglia, in which they modulate neuronal excitability. In this study we demonstrate that linopirdine acts as an agonist of TRPV1 (transient receptor potential vanilloid type 1), another ion channel expressed in nociceptors and involved in pain signaling. Linopirdine induces increases in intracellular calcium concentration in human embryonic kidney 293 (HEK293) cells expressing TRPV1, but not TRPA1 and TRPM8 or in wild-type HEK293 cells. Linopirdine also activates an inward current in TRPV1-expressing HEK293 cells that is almost completely blocked by the selective TRPV1 antagonist capsazepine. At low concentrations linopirdine sensitizes both recombinant and native TRPV1 channels to heat, in a manner that is not prevented by the Kv7-channel opener flupirtine. Taken together, these results indicate that linopirdine exerts an excitatory action on mammalian nociceptors not only through inhibition of the M current but also through activation of the capsaicin receptor TRPV1.
利诺吡啶是一种众所周知的电压门控钾通道（Kv7 或 KCNQ）家族阻断剂，可在哺乳动物神经元中产生所谓的 M 电流。Kv7 亚基也在背根神经节中的痛觉感受神经元中表达，在这些神经元中调节神经元兴奋性。在这项研究中，我们证明利诺吡啶作为瞬时受体电位香草酸类型 1（TRPV1）的激动剂起作用，TRPV1 是另一种在伤害感受器中表达并参与疼痛信号传导的离子通道。利诺吡啶在表达 TRPV1 的人胚肾 293（HEK293）细胞中诱导细胞内钙离子浓度增加，但在不表达 TRPA1 和 TRPM8 的野生型 HEK293 细胞中没有增加。利诺吡啶还在表达 TRPV1 的 HEK293 细胞中激活内向电流，该电流几乎完全被 TRPV1 的选择性拮抗剂辣椒素阻断。在低浓度下，利诺吡啶敏化重组和天然 TRPV1 通道对热的反应，这种敏化作用不受 Kv7 通道 opener 氟吡汀的阻止。综上所述，这些结果表明利诺吡啶对哺乳动物伤害感受器的兴奋作用不仅通过抑制 M 电流，而且通过激活辣椒素受体 TRPV1 来实现。
