title: Allosteric activation of sodium-calcium exchange by picomolar concentrations of cadmium.
abstract: Chinese hamster ovary cells expressing the bovine cardiac Na+-Ca2+ exchanger (NCX1.1) accumulated Cd2+ after a lag period of several tens of seconds. The lag period reflects the progressive allosteric activation of exchange activity by Cd2+ as it accumulates within the cytosol. The lag period was greatly reduced in cells expressing a mutant exchanger, Delta(241-680), that does not require allosteric activation by Ca2+ for activity. Non-transfected cells did not show Cd2+ uptake under the same conditions. In cells expressing NCX1.1, the lag period was nearly abolished following an elevation of the cytosolic Ca2+ concentration. Cytosolic Cd2+ concentrations estimated at 0.5-2 pm markedly stimulated the subsequent uptake of Ca2+ by Na+-Ca2+ exchange. Outward exchange currents in membrane patches from Xenopus oocytes expressing the canine NCX1.1 were rapidly and reversibly stimulated by 3 pm Cd2+ applied at the cytosolic membrane surface. Exchange currents activated by 3 pm Cd2+ were 40% smaller than currents activated by 1 mum cytosolic Ca2+. Current amplitudes declined by 30% and the rate of current development fell sharply upon repetitive applications of Na+ in the presence of 3 pm Cd2+. Cd2+ mimicked the anomalous inhibitory effects of Ca2+ on outward exchange currents generated by the Drosophila exchanger CALX1.1. We conclude that the regulatory sites responsible for allosteric Ca2+ activation bind Cd2+ with high affinity and that Cd2+ mimics the regulatory effects of Ca2+ at concentrations 5 orders of magnitude lower than Ca2+.
authors.affiliation: Institute of Cardiovascular Sciences, University of Manitoba, St Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada, R2H 2A6.
authors.forename: Hoa Dinh
authors.initials: HD
authors.lastname: Le
authors.forename: Alexander
authors.initials: A
authors.lastname: Omelchenko
authors.forename: Larry V
authors.initials: LV
authors.lastname: Hryshko
authors.forename: Alexandra
authors.initials: A
authors.lastname: Uliyanova
authors.forename: Madalina
authors.initials: M
authors.lastname: Condrescu
authors.forename: John P
authors.initials: JP
authors.lastname: Reeves
mesh_terms: D000818:Animals; D016466:CHO Cells; D002104:Cadmium / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D007536:Isomerism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D008832:Microchemistry; D009865:Oocytes / Q000187:drug effects / Q000502:physiology*; D019831:Sodium-Calcium Exchanger / Q000187:drug effects / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D019831:Sodium-Calcium Exchanger; D002104:Cadmium; D002118:Calcium