Tetraethylammonium (TEA), a K+ channel blocker, induced PRL secretion and an increase in cytosol Ca2+ concentration [Ca2+]i in a dose-dependent manner between 5-20 mM in GH4C1 rat pituitary tumor-derived cells. Removal of medium Ca2+ or the addition of 1 microM nifedipine abolished both the induced [Ca2+]i increment and PRL secretion. TEA augmented the TRH-induced rise in [Ca2+]i and inhibited the rise in [Ca2+]i induced by 30 mM K+. The dynamics of TEA-, TRH- and K(+)-induced PRL secretion were different, with the TEA-induced secretory peak occurring at about 10 min compared to 2-3 min for TRH and K+. Tolbutamide, which blocks ATP-sensitive K+ channels, induced PRL secretion without causing a rise in [Ca2+]i. The results suggest that: (a) K+ channels have a complex interaction with the PRL secretory process in GH4C1 cells; (b) TEA induces PRL secretion by causing Ca2+ influx through dihydropyridine-sensitive Ca2+ channels; and (c) K+ channels play a different role in the [Ca2+]i rise induced by TRH than in that induced by depolarizing K+.