Ferrous iron binding to epinephrine promotes the oxidation of iron and impedes activation of adrenergic receptors

Abstract

Upon release in response to stress, epinephrine (Epi) may interact with labile iron pool in human plasma with potentially important (patho)physiological consequences. We have shown that Epi and Fe³⁺ build stable 1:1 high-spin bidentate complex at physiological pH, and that Epi does not undergo degradation in the presence of iron. However, the interactions of Epi with the more soluble Fe²⁺, and the impact of iron on biological activity of Epi are still not known. Herein we showed that Epi and Fe²⁺ build colorless complex which is stable under anaerobic conditions. In the presence of O₂, Epi promoted the oxidation of Fe²⁺ and the formation of Epi-Fe³⁺ complex. Cyclic voltammetry showed that mid-point potential of Epi-Fe²⁺ complex is very low (-582 mV vs. standard hydrogen electrode), which explains catalyzed oxidation of Fe²⁺. Next, we examined the impact of iron binding on biological performance of Epi using patch clamping in cell culture with constitutive expression of adrenergic receptors. Epi alone evoked an increase of outward currents, whereas Epi in the complex with Fe³⁺ did not. This implies that the binding of Epi to adrenergic receptors and their activation is prevented by the formation of complex with iron. Pro-oxidative activity of Epi-Fe²⁺ complex may represent a link between chronic stress and cardiovascular problems. On the other hand, labile iron could serve as a modulator of biological activity of ligands. Such interactions may be important in human pathologies that are related to iron overload or deficiency.

Keywords: Adrenaline; Adrenergic receptor; Labile iron pool; Ligand; Oxidative stress; Reduction potential.