The effects of histamine on the membrane potential and currents of human glioblastoma (GL-15) cells were investigated. In perforated whole cell configuration, short (3 s) applications of histamine (100 microM) hyperpolarized the membrane by activating a K(+)-selective current. The response involved the activation of the pyrilamine-sensitive H(1) receptor and Ca(2+) release from thapsigargin-sensitive intracellular stores. The histamine-activated current was insensitive to tetraethylammonium (3 mM), iberiotoxin (100 nM), and d-tubocurarine (100 microM) but was markedly inhibited by charybdotoxin (100 nM), clotrimazole (1 microM), and 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34, 1 microM), a pharmacological profile congruent with the intermediate conductance Ca(2+)-activated K(+) (IK(Ca)) channel. Cell-attached recordings confirmed that histamine activated a K(+) channel with properties congruent with the IK(Ca) channel (voltage independence, 22 pS unitary conductance and slight inward rectification in symmetrical 140 mM K(+)). More prolonged histamine applications (2-3 min) often evoked a sustained IK(Ca) channel activity, which depended on a La(2+) (10 microM)-sensitive Ca(2+) influx. Intracellular Ca(2+) measurements revealed that the sustained IK(Ca) channel activity enhanced the histamine-induced Ca(2+) signal, most likely by a hyperpolarization-induced increase in the driving force for Ca(2+) influx. In virtually all cells examined we also observed the expression of the large conductance Ca(2+)-activated K(+) (BK(Ca)) channel, with a unitary conductance of ca. 230 pS in symmetrical 140 mM K(+), and a Ca(2+) dissociation constant [K(D(Ca))] of ca. 3 microM, at -40 mV. Notably in no instance was the BK(Ca) channel activated by histamine under physiological conditions. The most parsimonious explanation based on the different K(D(Ca)) for the two K(Ca) channels is provided.