We have recently shown that the PLC-inhibitor U73122 and its non PLC-inhibiting structural analogue U73343 suppressed G protein-activated inwardly rectifying K+ (GIRK, Kir3) channels as well as large conductance Ca2+-activated K+ (BK) channels in a highly selective fashion, with no effect on the intermediate conductance Ca2+-activated K+ (IK) channels or on closely related Kir family members such as IRK (Kir2) and ROMK (Kir). A first hint at a possible interaction site of U73122 and BK channels came from single channel recordings in the inside-out configuration, in which bath-applied U73122 and U73343 significantly slowed the ultrafast gating kinetics of BK channels at test potentials above +40 mV. In studies on the structure/function relationship of BK channels, similar alterations of channel gating had been attributed to modification of the C-terminus, in particular the RCK domains. In fact, alignments of the amino-acid sequences of the Kir-family and BK suggest that U73122, rather than directly blocking the pore, interacts with the C-terminal ends of BK and Kir3.1/2 to modify channel gating. To test this hypothesis we are currently examining several BK channel constructs, in which the C-terminus is modified at different sites.