Abstract
The Na+/K+-ATPase is a membrane ion-transporter protein, specifically inhibited by digitalis glycosides used in cardiac therapy. The existence in mammals of some endogenous digitalis-like factors (EDLFs) as presumed ATPase ligands is generally accepted. But the chemical structure of these factors remained elusive because no weighable amounts of pure EDLFs have been isolated. Recent high-resolution crystal structure data of Na+/K+-ATPase have located the hydrophobic binding pocket of the steroid glycoside ouabain. It remained uncertain if the EDLF are targeting this steroid-receptor or another specific binding site(s). Our recently disclosed spherical oligo-silicic acids (SOSA) fulfill the main criteria to be identified with the presumed EDL factors. SOSA was found as a very potent inhibitor of the Na+/K+-ATPase, Ca2+-ATPase, H+/K+-ATPase, and of K-dp-ATPase, with IC50 values between 0.2 and 0.5 μg/mL. These findings are even more astonishing while so far, neither monosilicic acid nor its poly-condensed forms have been remarked biologically active. With the diameter ϕ between 1 and 3 nm, SOSA still belong to molecular species definitely smaller than silica nano-particles with ϕ > 5 nm. In SOSA molecules, almost all Si-OH bonds are displayed on the external shell, which facilitates the binding to hydrophilic ATPase domains. SOSA is stable for long term in solution but is sensitive to freeze-drying, which could explain the failure of countless attempts to isolate pure EDLF. There is a strong resemblance between SOSA and vanadates, the previously known general inhibitors of P-type ATPases. SOSA may be generated endogenously by spherical oligomerization of the ubiquitously present monosilicic acid in animal fluids. The structure of SOSA is sensitive to the concentration of Na+, K+, Ca2+, Mg2+, and other ions suggesting a presumably archaic mechanism for the regulation of the ATPase pumps.
Highlights
Investigating the staircase effect on frog ventricular muscle, it was revealed in the early 1950s that human serum contains a factor, which improves the contractile power of the heart, similar to plantderived digitalis glycosides [1]
This kind of relationship between exogenous drug-substances, which fits accidentally into the receptor of a body’s own factor has been verified by the discovery of endorphins, the endogenous counterparts of the plant-derived morphine [3]. Why this broadly accepted rationale was not applied in the differentiation between endogenous digitalis-like factors (EDLFs) and exogenous digitalis glycosides is a subject of the present review
At the end of 1990s, we investigated at the Max-Planck Institute for Biochemistry in Munich an herbal product isolated from the roots of Helleborus species
Summary
Investigating the staircase effect on frog ventricular muscle, it was revealed in the early 1950s that human serum contains a factor, which improves the contractile power of the heart, similar to plantderived digitalis glycosides [1]. MCS factors interact with the Na+/K+-ATPase in the E1 conformation of the ion pump and induce a structural rearrangement that causes a change of the equilibrium dissociation constant for one of the first 2 intracellular cation binding sites. A possible activation mechanism could be by favoring the differentiate binding of Na+ ions to the E1 conformation and promoting the phosphorylation step Accepting this hypothesis, the generally found cytosolic level of [Na+] = 5.0 mM in the eukaryotic cells could be a consequence of the structural change of the archaic ligand SOSA, which happens accidentally at this Na+ ion concentration. The here proposed probably archaic regulatory mechanism of the NKA pump by ion-dependent structural changes of the endogenous ligand could work for other ATPases. This regulatory mechanism, assuming the ion-sensitive structural variation of the archaic ligand SOSA, can explain the astonishing manifoldness of the same well-conserved ion-pumping mechanism in the hitherto identified more than 200 different P-type ATPase pumps
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