Department of Medical Research, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 60002, Taiwan.
Department of Ophthalmology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 60002, Taiwan.
Int J Mol Sci. 2022 Jun 24;23(13):7042. doi: 10.3390/ijms23137042.
QO-58 (5-(2,6-dichloro-5-fluoropyridin-3-yl)-3-phenyl-2-(trifluoromethyl)-1H-pyrazolol[1,5-a]pyrimidin-7-one) has been regarded to be an activator of K7 channels with analgesic properties. However, whether and how the presence of this compound can result in any modifications of other types of membrane ion channels in native cells are not thoroughly investigated. In this study, we investigated its perturbations on M-type K current (), Ca-activated K current (), large-conductance Ca-activated K (BK) channels, and -mediated K current () identified from pituitary tumor (GH) cells. Addition of QO-58 can increase the amplitude of and in a concentration-dependent fashion, with effective EC of 3.1 and 4.2 μM, respectively. This compound could shift the activation curve of toward a leftward direction with being void of changes in the gating charge. The strength in voltage-dependent hysteresis (V) of evoked by upright triangular ramp pulse (V) was enhanced by adding QO-58. The probabilities of M-type K (K) channels that will be open increased upon the exposure to QO-58, although no modification in single-channel conductance was seen. Furthermore, GH-cell exposure to QO-58 effectively increased the amplitude of as well as enhanced the activity of BK channels. Under inside-out configuration, QO-58, applied at the cytosolic leaflet of the channel, activated BK-channel activity, and its increase could be attenuated by further addition of verruculogen, but not by linopirdine (10 μM). The application of QO-58 could lead to a leftward shift in the activation curve of BK channels with neither change in the gating charge nor in single-channel conductance. Moreover, cell exposure of QO-58 (10 μM) resulted in a minor suppression of amplitude in response to membrane hyperpolarization. The docking results also revealed that there are possible interactions of the QO-58 molecule with the KCNQ or K1.1 channel. Overall, dual activation of and caused by the presence of QO-58 eventually may have high impacts on the functional activity (e.g., anti-nociceptive effect) residing in electrically excitable cells. Care must be exercised when interpreting data generated with QO-58 as it is not entirely KCNQ/K7 selective.
QO-58（5-(2,6-二氯-5-氟吡啶-3-基）-3-苯基-2-(三氟甲基)-1H-吡唑并[1,5-a]嘧啶-7-酮）被认为是一种具有镇痛作用的 K7 通道激活剂。然而，目前尚不清楚该化合物的存在是否以及如何导致天然细胞中其他类型的膜离子通道发生变化。在这项研究中，我们研究了它对垂体肿瘤（GH）细胞中鉴定的 M 型 K 电流（）、钙激活的 K 电流（）、大电导钙激活的 K（BK）通道和 - 介导的 K 电流（）的干扰。QO-58 的添加可以以浓度依赖的方式增加 和 的幅度，有效 EC 分别为 3.1 和 4.2 μM。该化合物可以使 的激活曲线向左移位，而门控电荷不变。添加 QO-58 可增强由直立三角形斜坡脉冲（V）引起的电压依赖性滞后（V）的强度。QO-58 暴露后，M 型 K（K）通道的开放概率增加，尽管未见单通道电导发生变化。此外，GH 细胞暴露于 QO-58 可有效增加 幅度并增强 BK 通道活性。在细胞内模式下，QO-58 作用于通道的细胞质叶，激活 BK 通道活性，进一步添加疣孢菌素可减弱其增加，但不能用利诺吡啶（10 μM）减弱。QO-58 的应用可导致 BK 通道的激活曲线向左移位，门控电荷和单通道电导均无变化。此外，细胞暴露于 QO-58（10 μM）可导致对膜超极化的响应中 幅度略有抑制。对接结果还表明，QO-58 分子与 KCNQ 或 K1.1 通道之间可能存在相互作用。总的来说，QO-58 的存在对 和 的双重激活最终可能对电兴奋细胞的功能活动（例如，抗伤害感受作用）产生重大影响。在解释使用 QO-58 生成的数据时必须谨慎，因为它不完全是 KCNQ/K7 选择性的。
