Modulation of INa, Ih, and IK(erg) by Extracellular or Intracellular QX-314 (N-(2,6-dimethylphenylcarbamoylmethyl) triethylammonium bromide) in Pituitary Tumor Cells

QX-314 is a positively charged lidocaine derivative with the membrane-impermeant property. This compound applied at the intracellular side has been shown to suppress the voltage-gated Na⁺ current (<i>I</i>_Na), while lidocaine itself acts to suppress the hyperpolarization-activated cation current (<i>I</i>_h). To what extent this drug may exert any effects on various plasmalemmal ionic currents still remains largely unknown. This investigation focused on the impact of QX-314 on ionic currents in GH₃ cells derived from pituitary tumors. This compound applied extracellularly was noted to differentially suppress the amplitude of transient and late <i>I</i>_Na with an IC₅₀ value of 93 and 42 μM, respectively. In GH₃ cells dialyzed with QX-314 (10 μM), the <i>I</i>_Na(T) amplitude evoked by a brief depolarizing step was decreased, and its inactivation was increased. Moreover, QX-314, when applied extracellularly at 100 μM, diminished the amplitude of the <i>I</i>_h current with an IC₅₀ of 68 μM. Intracellular dialysis with QX-314 also suppressed <i>I</i>_h amplitude; moreover, the later application of oxaliplatin reversed this suppression. As cells were extracellularly and continually exposed to QX-314, the magnitude of the <i>erg</i>-mediated K⁺ current (<i>I</i>_K(erg)) was also effectively suppressed with an IC₅₀ value of 73 μM. Furthermore, upon intracellular dialysis with QX-314 (10 μM), the degree of the voltage-dependent hysteresis (Hys_(V)) of <i>I</i>_K(erg) during the long-lasting isosceles-triangular ramp voltage was decreased; during continued exposure to QX-314, further extracellular bath additions of PD118057 (10 μM) counteracted QX-314-induced suppression. However, the extracellular addition of QX-314 (100 μM) mildly suppressed the outward delayed rectifier K⁺ current in GH₃ cells. Collectively, QX-314 effectively suppressed <i>I</i>_Na, <i>I</i>_h, and <i>I</i>_K(erg) in GH₃ cells, a model of endocrine function, and these actions may contribute to their physiological functions, if similar effects are observed in vivo.