The effects of berberine, an isoquinoline alkaloid, were investigated in human myeloma cells. In cells with intracellular Ca2+ concentration ([Ca2+]i) = 10 nM, the depolarizing square pulses from -80 mV elicited an instantaneous outward current with an inactivation. This outward current was voltage dependent, activating at -30 mV and showed inactivation with repetitive depolarization, and was hence believed to be n type voltage-activated K+ current (IK(V)). Berberine (30 microM) produced a prolongation in the recovery of IK(V) inactivation. In cells with [Ca2+]i = 1 microM, berberine also inhibited A23187-induced IK(Ca). Berberine (1-300 microM) caused the inhibition of IK(V) and IK(Ca) in the concentration-dependent manners. The IC50 values of berberine-induced inhibition of IK(V) and IK(Ca) were approximately 15 microM and 50 microM, respectively. In inside-out configurations, berberine inside the pipette suppressed the activity of K(Ca) channels without changing the single channel conductance. Berberine also inhibited the proliferation of this cell line and the IC50 value of berberine-induced inhibition of cell proliferation was 5 microM. Thus, the cytotoxic effect of berberine in cancer cells may be partially explained by its direct blockade of these K+ channels.