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研究 XAV-939(一种端锚聚合酶抑制剂)对小鼠 MA-10 睾丸间质肿瘤细胞中 erg 介导的 K 电流密度和门控的影响。

Investigating the influence of XAV-939, a tankyrase inhibitor, on the density and gating of erg-mediated K currents in mouse MA-10 Leydig tumor cells.

机构信息

Department of Urology, An Nan Hospital, China Medical University, Tainan, 70965, Taiwan.

Department of Physiology, National Cheng Kung University Medical College, Tainan, Taiwan; School of Medicine, National Sun-Yat Sen University College of Medicine, Kaohsiung, Taiwan; Department of Medical Education and Research, An Nan Hospital, China Medical University, Tainan, Taiwan.

出版信息

Eur J Pharmacol. 2024 May 15;971:176518. doi: 10.1016/j.ejphar.2024.176518. Epub 2024 Mar 29.

Abstract

XAV-939(XAV) is a chemical compound that inhibits the activity of tankyrase. However, the precise way in which XAV alters membrane ionic currents is not well understood. In this study,our goal was to examine the impact of XAV on the ionic currents in mouse MA-10 Leydig cells, specifically focusing on the magnitude, gating properties,and voltage-dependent hysteresis of erg-mediated Kcurrents(I). In our whole-cell current recordings we observed that the addition of XAV inhibited the density of I in a concentration-dependent manner with an IC of 3.1 μM. Furthermore we found that continued exposure to XAV, further addition of neither liraglutide nor insulin-like growth factor-1 counteracted XAV-mediated inhibition of I. Additionally the presence of XAV suppressed the mean current versus voltage relationship of I across the entire voltage-clamp step analyzed. This compound shifted the steady-state activation curve of I to a less negative potential by approximately 12 mV. The presence of XAV increased the time constant of deactivating I in MA-10 cells. The voltage-dependent clockwise hysteresis of I responding to prolonged upright isosceles-triangular ramp voltage became diminished by adding XAV; moreover subsequent addition of NS3623 effectively reversed XAV-induced decrease of hysteretic area of I. XAV also inhibited the proliferation of this cell line and the IC value of XAV-induced inhibition of cell proliferation was 2.8M. Overall the suppression of I by XAV may serve as a significant ionic mechanism that contribute to the functional properties of MA-10 cells. However, it is important to note that this effect cannot be attributed solely to the inhibition of tankyrase.

摘要

XAV-939(XAV) 是一种抑制 Tankyrase 活性的化合物。然而,XAV 改变膜离子电流的确切方式尚不清楚。在这项研究中,我们的目标是研究 XAV 对小鼠 MA-10 间质细胞离子电流的影响,特别是关注 erg 介导的 K 电流(I)的幅度、门控特性和电压依赖性滞后。在我们的全细胞电流记录中,我们观察到 XAV 以浓度依赖性方式抑制 I 的密度,IC 为 3.1μM。此外,我们发现,持续暴露于 XAV 时,进一步加入利拉鲁肽或胰岛素样生长因子-1 并不能抵消 XAV 对 I 的抑制作用。此外,XAV 的存在抑制了 I 的平均电流与整个电压钳步分析的电压关系。这种化合物将 I 的稳态激活曲线向右移至约 12 mV 的更负电位。XAV 增加了 MA-10 细胞中 I 的失活时间常数。添加 XAV 后,I 对延长直立等腰三角形 ramp 电压的电压依赖性顺时针滞后减小;此外,随后加入 NS3623 可有效逆转 XAV 诱导的 I 滞后面积的减小。XAV 还抑制了该细胞系的增殖,XAV 诱导的细胞增殖抑制的 IC 值为 2.8M。总体而言,XAV 对 I 的抑制可能是导致 MA-10 细胞功能特性的重要离子机制。然而,需要注意的是,这种效应不能仅仅归因于 Tankyrase 的抑制。

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