The Effectiveness of Isoplumbagin and Plumbagin in Regulating Amplitude, Gating Kinetics, and Voltage-Dependent Hysteresis of Erg-Mediated K+ Currents.

Isoplumbagin (isoPLB, 5-hydroxy-3-methyl-1,4-naphthoquinone), a naturally occurring quinone, has been observed to exercise anti-inflammatory, antimicrobial, and antineoplastic activities. Notably, whether and how isoPLB, plumbagin (PLB), or other related compounds impact transmembrane ionic currents is not entirely clear. In this study, during GH3-cell exposure to isoPLB, the peak and sustained components of an erg (ether-à-go-go related gene)-mediated K+ current (IK(erg)) evoked with long-lasting-step hyperpolarization were concentration-dependently decreased, with a concomitant increase in the decaying time constant of the deactivating current. The presence of isoPLB led to a differential reduction in the peak and sustained components of deactivating IK(erg) with effective IC50 values of 18.3 and 2.4 μM, respectively, while the KD value according to the minimum binding scheme was estimated to be 2.58 μM. Inhibition by isoPLB of IK(erg) was not reversed by diazoxide; however, further addition of isoPLB, during the continued exposure to 4,4′-dithiopyridine, did not suppress IK(erg) further. The recovery of IK(erg) by a two-step voltage pulse with a geometric progression was slowed in the presence of isoPLB, and the decaying rate of IK(erg) activated by the envelope-of-tail method was increased in its presence. The strength of the IK(erg) hysteresis in response to an inverted isosceles-triangular ramp pulse was diminished by adding isoPLB. A mild inhibition of the delayed-rectifier K+ current (IK(DR)) produced by the presence of isoPLB was seen in GH3 cells, while minimal changes in the magnitude of the voltage-gated Na+ current were demonstrated in its presence. Moreover, the IK(erg) identified in MA-10 Leydig tumor cells was blocked by adding isoPLB. Therefore, the effects of isoPLB or PLB on ionic currents (e.g., IK(erg) and IK(DR)) demonstrated herein would be upstream of our previously reported perturbations on mitochondrial morphogenesis or respiration. Taken together, the perturbations of ionic currents by isoPLB or PLB demonstrated herein are likely to contribute to the underlying mechanism through which they, or other structurally similar compounds, result in adjustments in the functional activities of different neoplastic cells (e.g., GH3 and MA-10 cells), presuming that similar in vivo observations occur.