Ionophore 4-BrA23187 Transports Zn2+ and Mn2+ with High Selectivity Over Ca2

• Published in: Biochemistry (Easton) 1996-10, Vol.35 (43), p.13817-13825
• Main Authors: Erdahl, Warren L, Chapman, Clifford J, Wang, Exing, Taylor, Richard W, Pfeiffer, Douglas R
• Format: Article
• Language: English
• Subjects: Aminoquinolines - metabolism; Calcimycin - analogs & derivatives; Calcimycin - pharmacology; Calcium - metabolism; Cations - metabolism; Hydrogen-Ion Concentration; Ionomycin - pharmacology; Ionophores - metabolism; Ionophores - pharmacology; Kinetics; Liposomes - metabolism; Magnesium - metabolism; Models, Chemical; Models, Molecular; Molecular Structure; Valinomycin - metabolism; Valinomycin - pharmacology; Zinc - metabolism
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi961391q

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 μM concentration of the cations, A23187 displays the transport selectivity sequence Zn2+ > Mn2+ > Ca2+ > Co2+ > Ni2+ > Sr2+, with the absolute rates of transport spanning ∼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 ∼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+.