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One of the major successes of nuclear medicine in recent years has been the clinical utility of the 99mTc-labeled bone-imaging agents. This article is concerned with the evidence available for the mechanisms by which these and other such radiopharmaceuticals localize at sites in the skeleton.

Ionophore A23187 induced histamine release from peritoneal rat mast cells in the presence of lanthanum or terbium as it did in the presence of calcium. Low concentrations of lanthanides (10(-5) to 2 X 10(-4) M) were more efficient than similar concentrations of calcium. The effect of low concentrations of calcium and lanthanides were additive. Increasing the concentration of lanthanides above 10(-3) M decreased histamine release. This decrease was partly reversed by calcium. Calmodulin inhibitors, phenothiazines, R24571 and mepacrine, inhibited the histamine release induced by either calcium or lanthanides. Zn2+, a calmodulin inhibitor transported by A23187, inhibited more potently the calcium-dependent histamine release. Lanthanides decrease histamine release induced by 48/80 in the absence of added calcium. These data show that ionophore A23187 can transport lanthanides across the plasma membrane of mast cells, allowing the trivalent cations to substitute for calcium in the activation of calmodulin or calmoduline-like proteins.

Pulsed dye laser excitation spectroscopy of the 7F0----5D0 transition of Eu(III) reveals only a single peak as this ion is titrated into apocalmodulin. A titration based on the intensity of this transition shows that the first two Eu(III) ions bind quantitatively to two tight sites, followed by weaker binding (Kd = 2 microM) to two additional sites under conditions of high ionic strength (0.5 M KC1). This excitation experiment is also shown to be a general method for measuring contaminating levels of EDTA down to 0.2 microM in proton solutions. Experiments with Tb(III) using both direct laser excitation and indirect sensitization of Tb(III) luminescence through tyrosine residues in calmodulin also give evidence for two tight and two weaker binding sites (Kd = 2-3 microM). The indirect sensitization results primarily upon binding to the two weaker sites, implying that Tb(III) binds first to domains I and II, which are remote from tyrosine-containing domains III and IV. The 7F0----5D0 excitation signal of Eu(III) was used to measure the relative overall affinities of the tripositive lanthanide ions, Ln(III), across the series. Ln(III) ions at the end of the series are found to bind more weakly than those at the beginning and middle of the series. Eu(III) excited-state lifetime measurements in H2O and D2O reveal that two water molecules are coordinated to the Eu(III) at each of the four metal ion binding sites. Measurements of Förster-type nonradiative energy-transfer efficiencies between Eu(III) and Nd(III) in the two tight sites were carried out by monitoring the excited-state lifetimes of Eu(III) in the presence and absence of the energy acceptor ion Nd(III).(ABSTRACT TRUNCATED AT 250 WORDS)

Emission Mössbauer spectra and Perturbed Angular Correlation measurements have been performed on samples of mineral bone powder labelled with 161Tb3+ or 133Ba2+ ions after either in vitro absorption or uptake by metabolic pathway. The study of these hyperfine spectra, compared with those carried out when 161Tb or 133Ba are situated in either hydroxyde lattice or phosphate one, shows that the uptake modes of rare-and alkaline-earth ions on the bone matrix are different. The rare earth ion seems to be absorbed on the surface bone in an environment of hydroxyl groups similar to the structure of a rare earth hydroxyde. The alkaline earth ion bone uptake appears more complicated and would make according to the following process : at first, surface absorption on the hydroxylapatite in a hydroxyde environment and then cationic exchange with the calcium phosphate groups into bone crystals.

Yeast inorganic pyrophosphatase has three roles for metal ions in its reaction: activator, substrate and structural. Out of a wide variety of metal ions tested, only Mg2+, Zn2+, mn2+ and Co2+ can fulfill both the activator and substrate roles. Several other metal ions inhibit the Mg2+-stimulated activity; the strong inhibition by Ca2+ (and probably Cd2+) is due to interference with both activator and substrate roles, while the weaker inhibition by Sr2+ (and possibly Cu2+ and Ni2+) is due to interference with only the substrate role. Rare earth ions strongly stimulate nonenzymic PPi hydrolysis but do not activate the enzyme. Despite its ability to fulfill both the activator and substrate roles. Zn2+ causes inactivation of the enzyme, probably by interference with the "structural" Mg2+. The results suggest that the three roles for metal ions are independent (an individual metal ion can satisfy only one at a time) and that the metal ion specificity for the three roles declines in the order: structural greater than substrate greater than activator.

The high-affinity Ca2+-binding sites of cardiac sarcoplasmic reticulum (Ca2+ +Mg2+)-ATPase have been probed using trivalent lanthanide ions. Non-radiative energy-transfer studies, using luminescent probe Eu3+ as a donor and Nd3+ or Pr3+ as acceptor, were carried out to estimate the distance between two high-affinity Ca2+-binding/transport sites. Eu3+ was excited directly with pulsed laser light and the energy-transfer efficiency to Nd3+ or Pr3+ was measured, under the conditions in which most donor-acceptor pairs occupied the high-affinity Ca2+ sites. The distance between two high-affinity Ca2+ sites is about 0.89 nm. In the presence of ATP the distance between the high-affinity sites is about 0.855 nm, whereas in the presence of adenosine 5'-[beta, gamma-methylene]triphosphate or adenosine 5'-[beta, gamma-imino]triphosphate the distance is about 0.895 nm. To estimate the distance between the high-affinity Ca2+ sites and ATP-binding/hydrolytic site, we have measured the energy-transfer efficiency between Eu3+ and Cr3+-ATP with Eu3+ at the high-affinity Ca2+ sites and Cr3+-ATP at the ATP-binding/hydrolytic site. Our results show that ATP-binding/hydrolytic site is separated by about 2.2 nm from each high-affinity Ca2+ site.