Ionophore 4-BrA23187 transports Zn2+ and Mn2+ with high selectivity over Ca2+.
The cation transport selectivities of the Ca2+ ionophores A23187, Ionomycin, and 4-BrA23187 have been determined using a model system comprised of phospholipid vesicles loaded with the chelator/indicator Quin-2. At pH 7.00 and a 100 microM concentration of the cations, A23187 displays the transport selectivity sequence Zn2+ > Mn2+ > Ca2+ > Co2+ > Ni2+ > Sr2+, with the absolute rates of transport spanning approximately 3 orders of magnitude. Similar data are obtained with Ionomycin, although the relative transport rates of Zn2+ and Mn2+ are equivalent, and the range of absolute rates is decreased by a factor of approximately 3. When values are normalized to those of Ca2+, transport selectivity is seen to be only weakly related to complexation or extraction selectivity. It is also seen that, when used to manipulate Ca2+ (or Mg2+), both ionophores can be expected to alter the distribution of additional divalent cations which have known biological activities. 4-BrA23187 is a low-activity ionophore for Ca2+, compared to A23187 and Ionomycin, while retaining comparable activities as an ionophore for the other cations. As a consequence, 4-BrA23187 is highly selective for the transport of Zn2+ and Mn2+, compared to Ca2+, with selectivity ratios approaching that of valinomycin for K+ over Na+ when conditions are optimal. Plots of the log of the rate of cation transport vs the log of the ionophore concentration indicate that Ca2+ is transported primarily as a 2:1 complex by A23187 and 4-BrA23187, but Zn2+ and Mn2+ are transported, in part, as 1:1 complexes. These findings, together with a postulated low stability of 2:1, compared to 1:1 complexes between 4-BrA23187 and divalent cations, partially explain the novel transport selectivity of this compound. Unlike A23187 or Ionomycin, 4-BrA23187 may be useful for investigating cell regulation by Zn2+ and Mn2+, without interference by regulatory mechanisms which respond to Ca2+.
Department of Medical Biochemistry, College of Medicine, Ohio State University, Columbus 43210, USA.
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Erdahl
C J
CJ
Chapman
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Wang
R W
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Taylor
D R
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Pfeiffer
D000634:Aminoquinolines / Q000378:metabolism; D000001:Calcimycin / Q000031:analogs & derivatives / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002412:Cations / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D008081:Liposomes / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism*; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D014634:Valinomycin / Q000378:metabolism / Q000494:pharmacology; D015032:Zinc / Q000378:metabolism*
D000634:Aminoquinolines; D002412:Cations; D007476:Ionophores; D008081:Liposomes; D014634:Valinomycin; D000001:Calcimycin; D015759:Ionomycin; C033170:4-bromo-A-23187; D008274:Magnesium; D015032:Zinc; C035739:Quin2; D002118:Calcium