Caffeine enhancement of electrical activity through direct blockade of inward rectifying K+ currents in GH3 rat anterior pituitary cells

Treatment of rat anterior pituitary GH₃ cells with caffeine causes a reversible enhancement of electrical activity superimposed over a depolarization of the plasma membrane potential. Similar results are obtained with theophylline, but not with isobutylmethylxanthine or forskolin. The effects of caffeine are not related to Ca²⁺ liberation from intracellular stores since they are not affected by incubation of the cells with ryanodine or thapsigargin. Furthermore, caffeine-induced hyperpolarization of the membrane is not detectable even in cells in which Ca²⁺ liberation from inositol 1,4,5-trisphosphate-sensitive compartments produces a prominent transient hyperpolarization in response to thyrotropin-releasing hormone. Reductions of Ca²⁺-dependent K⁺ currents caused by partial block of L-type Ca²⁺ channels by caffeine are not sufficient to explain the effects of the xanthine, since the results obtained with caffeine are not mimicked by direct blockade of Ca²⁺ channels with nisoldipine. GH₃ cell inwardly rectifying K⁺ currents are inhibited by caffeine. Studies on the voltage dependence of the caffeine-induced effects indicate a close correlation between alterations of electrical parameters and reported values of steady-state voltage dependence of inactivation of these currents. We conclude that, as previously shown for thyrotropin-releasing hormone, modulation of inwardly rectifying K⁺ currents plays a major role determining the firing rate of GH₃ cells and its enhancement by caffeine.