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

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 K⁺currents(I_K(erg)). In our whole-cell current recordings we observed that the addition of XAV inhibited the density of I_K(erg) in a concentration-dependent manner with an IC₅₀ 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_K(erg). Additionally the presence of XAV suppressed the mean current versus voltage relationship of I_K(erg) across the entire voltage-clamp step analyzed. This compound shifted the steady-state activation curve of I_K(erg) to a less negative potential by approximately 12 mV. The presence of XAV increased the time constant of deactivating I_K(erg) in MA-10 cells. The voltage-dependent clockwise hysteresis of I_K(erg) 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_K(erg). XAV also inhibited the proliferation of this cell line and the IC₅₀ value of XAV-induced inhibition of cell proliferation was 2.8M. Overall the suppression of I_K(erg) 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.

Keywords: Erg-mediated K(+) current; Leydig cells; Voltage-dependent hysteresis; XAV-939 (5-[[[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl]amino]methyl]-2-thiophenecarboxylic acid ethyl ester); cell growth.