DIFFERENTIAL-EFFECTS OF HEAVY-METAL IONS ON CA2-DEPENDENT K+ CHANNELS()

1. The ability of various divalent metal ions to substitute for Ca2+ i n activating distinct types of Ca2+-dependent K+ [K+(Ca2+)] channels h as been investigated in excised, inside-out membrane patches of human erthrocytes and of clonal N1E-115 mouse neuroblastoma cells using the patch clamp technique. The effects of the various metal ions have been compared and related to the effects of Ca2+. 2. At concentrations bet ween 1 and 100 mu M Pb2+, Cd2+ and Co2+ activate intermediate conducta nce K+(Ca2+) channels in erythrocytes and large conductance K+(Ca2+) c hannels in neuroblastoma cells. Pb2+ and Co2+, but not Cd2+, activate small conductance K+(Ca2+) channels in neuroblastoma cells. Mg2+ and F e2+ do not activate any of the K+(Ca2+) channels. 3. Rank orders of th e potencies for K+(Ca2+) activation are Pb2+, Cd2+ > Ca2+, Co2+ >> Mg2 +, Fe2+ for the intermediate erythrocyte K+(Ca2+) channel, and Pb2+, C d2+ > Ca2+ > Co2+ >> Mg2+, Fe2+ for the small, and Pb2+ > Ca2+ > Co2>> Cd2+, Mg2+, Fe2+ for the large K+(Ca2+) channel in neuroblastoma ce lls. 4. At high concentrations Pb2+, Cd2+, and Co2+ block K+(Ca2+) cha nnels in erythrocytes by reducing the opening frequency of the channel s and by reducing the single channel amplitude. The potency orders of the two blocking effects are Pb2+ > Cd2+, Co2+ >> Ca2+, and Cd2+ > Pb2 +, Co2+, Ca2+, respectively, and are distinct from the potency orders for activation. 5. It is concluded that the different subtypes of K+(C a2+) channels contain distinct regulatory sites involved in metal ion binding and channel opening. The K+(Ca2+) channel in erythrocytes appe ars to contain additional metal ion interaction sites involved in chan nel block.