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

Article

Author: Wu, Sheng-Nan ; Ng, Woei-Ming ; So, Edmund Cheung ; Huang, Bu-Miin

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.

01 Nov 2019·Biochemical PharmacologyQ2 · MEDICINE

Pharmacological enhancement of repolarization reserve in human induced pluripotent stem cells derived cardiomyocytes

Q2 · MEDICINE

Article

Author: Goodrow, Robert J ; Haedo, Rodolfo J ; Bot, Corina T ; Treat, Jacqueline A ; Cordeiro, Jonathan M

BACKGROUNDHuman induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for many applications including safety pharmacology. However, a deficiency or complete absence of several K⁺ currents suggests repolarization reserve is low in hiPSC-CMs. We determined whether a dual I_to and I_Kr activator can improve repolarization reserve in hiPSC-CMs resulting in a more electrophysiologically mature phenotype.METHODS AND RESULTSHuman iPSC were maintained on growth factor and differentiated into the cardiac phenotype by addition of selective Wnt molecules. Current and voltage clamp recordings in single cells were made using patch electrodes. Extracellular field potentials were made using a microelectrode array on hiPSC monolayers. Action potential recordings from hiPSC-CMs following application of an I_Kr inhibitor resulted in depolarization of the membrane potential and prolongation of the APD. A flattening of the T-wave was noted on the pseudo-ECG. In contrast, application of the I_Kr and I_to agonist, NS3623, resulted in hyperpolarization of the membrane, slowing of the spontaneous rate and shortening of the APD. Voltage clamp recording showed a significant increase in I_Kr; no enhancement of I_to in hiPSC-CMs was noted. AP clamp experiments revealed that I_Kr plays a role in both phase 3 repolarization and phase 4 depolarization. mRNA analysis revealed that KCNH2 is abundantly expressed in hiPSC-CM, consistent with electrophysiological recordings.CONCLUSIONSAlthough NS3623 is a dual I_to and I_Kr activator in ventricular myocytes, application of this compound to hiPSC-CMs enhanced only I_Kr and no effect on I_to was noted. Our results suggest I_Kr enhancement can improve repolarization reserve in this cell type. The disconnect between a dramatic increase in I_to in adult myocytes versus the lack of effect in hiPSC-CMs suggest that the translation of pharmacological effects in hiPSC-CM to adult myocytes should be viewed with caution.

01 Apr 2018·Biochemical PharmacologyQ2 · MEDICINE

Regulation of Kv4.3 and hERG potassium channels by KChIP2 isoforms and DPP6 and response to the dual K + channel activator NS3623

Q2 · MEDICINE

Article

Author: Hancox, Jules C ; Doray, Adélaïde ; Lainez, Sergio ; Cannell, Mark B

Transient outward potassium current (I_to) contributes to early repolarization of many mammalian cardiac action potentials, including human, whilst the rapid delayed rectifier K⁺ current (I_Kr) contributes to later repolarization. Fast I_to channels can be produced from the Shal family KCNDE gene product Kv4.3s, although accessory subunits including KChIP2.x and DPP6 are also needed to produce a near physiological I_to. In this study, the effect of KChIP2.1 & KChIP2.2 (also known as KChIP2b and KChIP2c respectively), alone or in conjunction with the accessory subunit DPP6, on both Kv4.3 and hERG were evaluated. A dual I_to and I_Kr activator, NS3623, has been recently proposed to be beneficial in heart failure and the action of NS3623 on the two channels was also investigated. Whole-cell patch-clamp experiments were performed at 33 ± 1 °C on HEK293 cells expressing Kv4.3 or hERG in the absence or presence of these accessory subunits. Kv4.3 current magnitude was augmented by co-expression with either KChIP2.2 or KChIP2.1 and KChIP2/DPP6 with KChIP2.1 producing a greater effect than KChIP2.2. Adding DPP6 removed the difference in Kv4.3 augmentation between KChIP2.1 and KChIP2.2. The inactivation rate and recovery from inactivation were also altered by KChIP2 isoform co-expression. In contrast, hERG (Kv11.1) current was not altered by co-expression with KChIP2.1, KChIP2.2 or DPP6. NS3623 increased Kv4.3 amplitude to a similar extent with and without accessory subunit co-expression, however KChIP2 isoforms modulated the compound's effect on inactivation time course. The agonist effect of NS3623 on hERG channels was not affected by KChIP2.1, KChIP2.2 or DPP6 co-expression.

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