DEMONSTRATION OF AN INWARDLY RECTIFYING K-RELEASING-HORMONE AND CAFFEINE IN GH(3) RAT ANTERIOR-PITUITARY-CELLS( CURRENT COMPONENT MODULATEDBY THYROTROPIN)

Reduction of an inwardly rectifying K+ current by thyrotropin-releasin g hormone (TRH) and caffeine has been considered to be an important de terminant of electrical activity increases in GH(3) rat anterior pitui tary cells. However, the existence of an inwardly rectifying K+ curren t component was recently regarded as a misidentification of an M-like outward current, proposed to be the TRH target in pituitary cells, inc luding GH(3) cells. In this report, an inwardly rectifying component o f K+ current is indeed demonstrated in perforated-patch voltage-clampe d GH(3) cells. The degree of rectification varied from cell to cell, b ut both TRH and caffeine specifically blocked a fraction of current wi th strong rectification in the hyperpolarizing direction. Use of ramp pulses to continuously modify the membrane potential demonstrated a pr ominent blockade even in cells with no current reduction at voltages a t which M-currents are active. Depolarization steps to positive voltag es at the maximum of the inward current induced a caffeine-sensitive i nstantaneous outward current followed by a single exponential decay, T he magnitude of this current was modified in a biphasic way according to the duration of the previous hyperpolarization step. The kinetic ch aracteristics of the current are compatible with the possibility that removal from inactivation of a fast-inactivating delayed rectifier cau ses the hyperpolarization-induced current. Furthermore, the inwardly r ectifying current was blocked by astemizole, a potent and selective in hibitor of human ether-a-go-go -related gene (HERG) K+ channels. Along with other pharmacological and kinetic evidence, this indicates that the secretagogue-regulated current is probably mediated by a HERG-like K+ channel. Addition of astemizole to current-clamped cells induced c lear increases in the frequency of action potential production. Thus, an inwardly-rectifying K+ current and not an M-like outward current se ems to be involved in TRH and caffeine modulation of electrical activi ty in GH(3) cells.