1. The voltage-dependent inwardly rectifying K+ current (IK,IR) of clonal rat anterior pituitary cells (GH3/B6) was investigated in solutions with physiological K+ gradient using giant polynuclear cells. 2. IK,IR was isolated by the use of the selective erg (ether-à-go-go-related gene) channel blocker E-4031. In external 5 mM K+ solution, IK,IR carried steady-state outward current in the potential range between -60 and 0 mV, with a maximum current amplitude at -40 mV. Negative to the K+ equilibrium potential, EK, large transient inward currents occurred. 3. A selective pharmacological block of IK,IR induced a sustained depolarization of the membrane potential when Ca2+ action potentials were blocked, confirming the contribution of IK,IR to the resting membrane potential of GH3/B6 cells. 4. Thyrotrophin-releasing hormone (TRH) reduced effectively the sustained outward and the transient inward IK,IR. The magnitude of a TRH-induced depolarization of the membrane potential was consistent with an almost complete reduction of IK,IR. 5. The results demonstrate that the TRH-induced reduction of IK,IR is able to mediate the resting potential depolarization, suggesting that the increase in the frequency of action potentials occurring during the second phase of the TRH response in GH cells should be sustained by IK,IR inhibition. Moreover, this is the first evidence of a ligand-induced physiological modulation of an erg-mediated current.
