Differential effects of heavy metal ions on Ca(2+)-dependent K+ channels.
1. The ability of various divalent metal ions to substitute for Ca2+ in activating distinct types of Ca(2+)-dependent K+ [K+(Ca2+)] channels has 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 between 1 and 100 microM Pb2+, Cd2+ and Co2+ activate intermediate conductance K+(Ca2+) channels in erythrocytes and large conductance K+(Ca2+) channels in neuroblastoma cells. Pb2+ and Co2+, but not Cd2+, activate small conductance K+(Ca2+) channels in neuroblastoma cells. Mg2+ and Fe2+ do not activate any of the K+(Ca2+) channels. 3. Rank orders of the potencies for K+(Ca2+) activation are Pb2+, Cd2+ > Ca2+, Co2+ >> Mg2+, Fe2+ for the intermediate erythrocyte K+(Ca2+) channel, and Pb2+, Cd2+ > Ca2+ > Co2+ >> Mg2+, Fe2+ for the small, and Pb2+ > Ca2+ > Co2+ >> Cd2+, Mg2+, Fe2+ for the large K+(Ca2+) channel in neuroblastoma cells. 4. At high concentrations Pb2+, Cd2+, and Co2+ block K+(Ca2+) channels in erythrocytes by reducing the opening frequency of the channels 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+(Ca2+) channels contain distinct regulatory sites involved in metal ion binding and channel opening. The K+(Ca2+) channel in erythrocytes appears to contain additional metal ion interaction sites involved in channel block.
Vijverberg
H P
HP
Research Institute of Toxicology, Utrecht University, The Netherlands.
Leinders-Zufall
T
T
van Kleef
R G
RG
D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D002413:Cations, Divalent / Q000494:pharmacology*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000494:pharmacology; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000502:physiology; D004912:Erythrocytes / Q000187:drug effects / Q000502:physiology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008670:Metals / Q000494:pharmacology*; D051379:Mice; D009447:Neuroblastoma; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011336:Probability; D014407:Tumor Cells, Cultured
D002413:Cations, Divalent; D008670:Metals; D015221:Potassium Channels; D004533:Egtazic Acid; D002118:Calcium