A novel inward-rectifying K+ current with a cell-cycle dependence governs the resting potential of mammalian neuroblastoma cells

1. Human and murine neuroblastoma cell lines were used to investigate, by the whole-cell patch-clamp technique, the properties of a novel inward-rectifying K+ current (I-IR) in the adjustment of cell resting potential (V-rest), which was in the range -40 to -20 mV. 2. When elicited from a holding potential of 0 mV, I-IR was completely inactivated with time constants ranging from 13 ms at -140 mV to 4.5 s at -50 mV. The steady-state inactivation curve (h(V)) was found to be independent of [Na+](0) and [K+](0) (2-80 mM) and could be fitted to a Boltzmann curve with a steep slope factor of 5-6, and a V-1/2 around V-rest. Divalent ion-free extracellular solutions shifted h(V) to the left by about 28 mV. 3. Peak chord conductance, whose maximal value was approximately proportional to the square root of [K+](0), could be fitted to a Boltzmann curve independently of [K+](0), with a V-1/2 value around -48 mV and a slope factor of 18. Extracellular Cs+ and Ba2+ blocked the I-IR in a concentration- and voltage-dependent manner, but Ba2+ was less effective than it is on classical inward-rectifier channels. 4. Under control culture conditions the values of V-rest and V-1/2 of h(V) varied widely among cells. The knowledge of V-1/2 proved crucial for the theoretical prediction of V-rest. After cell synchronization in the G(0)-G(1) phase of the cell cycle, or at the G(1)-S boundaries, the cells reduced their variability of h(V). The same occurred after cell synchronization in G(1) by treatment with retinoic acid. 5. The experimental data could be fitted to a classical model of an inward rectifier, after removing the dependence of conductance activation on (V - E(K)), and incorporating an inactivation with an intrinsic voltage dependence. Moreover, the model predicts, for this novel inward rectifier and in contrast with the classical inward rectifier, the incapacity of maintaining, in physiological media, a V-rest more negative than -35 to -40 mV, which is an important feature of cancer cells.