Abstract
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(Na)), while lidocaine itself acts to suppress the hyperpolarization-activated cation current (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 GH(3) cells derived from pituitary tumors. This compound applied extracellularly was noted to differentially suppress the amplitude of transient and late I(Na) with an IC(50) value of 93 and 42 μM, respectively. In GH(3) cells dialyzed with QX-314 (10 μM), the 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(h) current with an IC(50) of 68 μM. Intracellular dialysis with QX-314 also suppressed 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 erg-mediated K(+) current (I(K(erg))) was also effectively suppressed with an IC(50) value of 73 μM. Furthermore, upon intracellular dialysis with QX-314 (10 μM), the degree of the voltage-dependent hysteresis (Hys((V))) of 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 GH(3) cells. Collectively, QX-314 effectively suppressed I(Na), I(h), and I(K(erg)) in GH(3) cells, a model of endocrine function, and these actions may contribute to their physiological functions, if similar effects are observed in vivo.