Dual modulation of K channels by thyrotropin-releasing hormone in clonal pituitary cells

Transmembrane electrical activity in pituitary tumor cells can be altered by substances that either stimulate or inhibit their secretory activity. Using patch recording techniques, we have measured the resting membrane potentials, action potentials, transmembrane macroscopic ionic currents, and single Ca²⁺-activated K channel currents of GH3 and GH4/C1 rat pituitary tumor cells in respone to thyrotropin-releasing hormone (TRH). TRH, which stimulates prolactin secretion, causes a transient hyperpolarization of the membrane potential followed by a period of elevated action potential frequency. In single cells voltage clamped and internally dialyzed with solutions containing K⁺, TRH application results in a transient increase in Ca²⁺-activated K currents and a more protracted decrease in voltage-dependent K currents. However, in cells internally dialyzed with K⁺-free solutions, TRH produces no changes in inward Ca²⁺ or Ba²⁺ currents through voltage-dependent Ca channels. The time courses of the effects on Ca²⁺-activated and voltage-dependent K currents correlate with the phases of hyperpolarization and hyperexcitability, respectively. During application of TRH to whole cells, single Ca²⁺-activated K channel activity increases in cell-attached patches not directly exposed to TRH. In contrast, TRH applied directly to excised membrane patches produces no change in single Ca²⁺-activated K channel behavior. We conclude that TRH (i) triggers intracellular Ca²⁺ release, which opens Ca²⁺-activated K channels, (ii) depresses voltage-dependent K channels during the hyperexcitable phase, which further elevated intracellular Ca²⁺, and (iii) does not directly modulate Ca channel activity.