Electrogenic and nonelectrogenic ion fluxes across lipid and mitochondrial membranes mediated by monensin and monensin ethyl ester

Abstract

Monensin is a carrier of cations through lipid membranes capable of exchanging sodium (potassium) cations for protons by an electroneutral mechanism, whereas its ethyl ester derivative ethyl-monensin is supposed to transport sodium (potassium) cations in an electrogenic manner. To elucidate mechanistic details of the ionophoric activity, ion fluxes mediated by monensin and ethyl-monensin were measured on planar bilayer lipid membranes, liposomes, and mitochondria. In particular, generation of membrane potential on liposomes was studied via the measurements of rhodamine 6G uptake by fluorescence correlation spectroscopy. In mitochondria, swelling experiments were expounded by the additional measurements of respiration, membrane potential, and matrix pH. It can be concluded that both monensin and ethyl-monensin can perform nonelectrogenic exchange of potassium (sodium) ions for protons and serve as electrogenic potassium ion carriers similar to valinomycin. The results obtained are in line with the predictions based on the crystal structures of the monensin complexes with sodium ions and protons (Huczyński et al., Biochim. Biophys. Acta, 1818 (2012) pp. 2108-2119). The functional activity observed for artificial membranes and mitochondria can be applied to explain the activity of ionophores in living systems. It can also be important for studying the antitumor activity of monensin.

One‐pot synthesis and antiproliferative activity of novel double‐modified derivatives of the polyether ionophore monensin A

“…The double-modified MON derivatives have been synthesized by the reaction of MON with triphosgene as an activating reagent and the respective alcohol or amine leading to obtain ten double-modified ester-carbonate derivatives (2)(3)(4)(5)(6)(7)(8)(9)(10)(11) and five double-modified amide-carbonate derivatives (12)(13)(14)(15)(16) with yields from 14% up to 82%, respectively (Supporting information Table S1). …”

“…These changes disturb the Na+/K+ concentration gradient and intracellular pH and lead to cell failure (mitochondrial injury, cell swelling, vacuolization) and finally to apoptosis. [12][13][14] In parallel, high antiproliferative activity of MON derivatives is probably associated with their mechanism of cation transport. MON inhibits the growth of colon cancer, lymphoma, and myeloma cells by inducing cell cycle arrest and apoptosis.…”

“…[5] Recently, it has been shown that in addition to its antibiotic activity, MON also presents very high antiproliferative activity. [12,15] Our previous efforts toward the synthesis of a variety of bioconjugates of MON with several Cinchona alkaloids and flavonolignan such as silybin as well as MON amides led to the development of efficient anticancer agents. Additionally, potential cytotoxicity of this ionophore against immunotoxins and its role in overcoming the multidrug resistance (MDR) of cancer cells has been documented.…”

“…T A B L E 1 Antiproliferative activity of MON and its derivatives (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Data are given as IC 50 The IC 50 value is defined as the concentration of a compound at which 50% growth inhibition is observed.…”

Manipulation of Transmembrane Transport by Synthetic K+ Ionophore Depsipeptides and Its Implications in Glucose‐Stimulated Insulin Secretion in β‐Cells

“…At physiological pH, it is expected that the carboxylic acid group of JG115B exists in its anionic form. Therefore the active species JG115B − ⋅ K + is a neutral zwitterionic complex that acts in electroneutral transport activity as a monovalent cation:proton antiporter . The rest of the compounds have no acidic groups, and therefore the complexes JG100⋅ K + , JG121⋅ K + , and JG115⋅ K + are positively charged species with electrogenic K + transport activity across lipid bilayers.…”