Stable potassium isotopes (41K/39K) track transcellular and paracellular potassium transport in biological systems

Abstract

As the most abundant cation in archaeal, bacterial, and eukaryotic cells, potassium (K+) is an essential element for life. While much is known about the machinery of transcellular and paracellular K transport–channels, pumps, co-transporters, and tight-junction proteins—many quantitative aspects of K homeostasis in biological systems remain poorly constrained. Here we present measurements of the stable isotope ratios of potassium (41K/39K) in three biological systems (algae, fish, and mammals). When considered in the context of our current understanding of plausible mechanisms of K isotope fractionation and K+ transport in these biological systems, our results provide evidence that the fractionation of K isotopes depends on transport pathway and transmembrane transport machinery. Specifically, we find that passive transport of K+ down its electrochemical potential through channels and pores in tight-junctions at favors 39K, a result which we attribute to a kinetic isotope effect associated with dehydration and/or size selectivity at the channel/pore entrance. In contrast, we find that transport of K+ against its electrochemical gradient via pumps and co-transporters is associated with less/no isotopic fractionation, a result that we attribute to small equilibrium isotope effects that are expressed in pumps/co-transporters due to their slower turnover rate and the relatively long residence time of K+ in the ion pocket. These results indicate that stable K isotopes may be able to provide quantitative constraints on transporter-specific K+ fluxes (e.g., the fraction of K efflux from a tissue by channels vs. co-transporters) and how these fluxes change in different physiological states. In addition, precise determination of K isotope effects associated with K+ transport via channels, pumps, and co-transporters may provide unique constraints on the mechanisms of K transport that could be tested with steered molecular dynamic simulations.

Exploring the K isotope composition of Göttingen minipig brain regions, and implications for Alzheimer's disease

“… 14 and Higgins et al. 79 (Note: data for δ 41 K are indicative only, as isotopic composition varies considerably both within and between animal models.)…”

“… Plots of δ 41 K for the single- and double-transgenic AD model animals in the current work as a function of concentration for biologically relevant elements (biometals and P) and δ 44 Ca (color coded as mentioned earlier). Reproducibility of measurements via Q–ICP–MS was better than 5% (RSD) for all elements, 79 and symbols encompass analytical error; analytical uncertainties for K isotope measurements in Table 2 . Statistically significant relations were determined for Mg(*), P(**), Fe(*), and Cu(*).…”

“… 90 and preprint of Higgins et al. 79 ). With these caveats well noted, the data nevertheless provide insight into the K isotope systematics of the brain and how such data might be expanded upon and utilized in for future aimed at the development of disease biomarkers such as those for AD.…”

“… 78 ; additionally they 78 analysed Seronorm (human) blood serum with a determined average δ 41 K of −0.30 ± 0.04‰, which is also resolvably higher than brain δ 41 K compositions determined herein. While still in the preprint phase (at time of writing) and not strictly comparable for δ 41 K due to normalization to diet/plasma, the work of 79 also determined that in R. norvegicus (common brown rat), blood plasma has significantly higher δ 41 K relative to the brain (cerebrum average δ 41 K of −0.25 ± 0.15‰; cerebellum average δ 41 K of −0.38 ± 0.21‰, relative to plasma) (and red blood cell, RBC, average δ 41 K of 0.40 ± 0.08‰). Cumulatively, these observations—coupled with the fact that 98% of bodily K is bound in muscle, skin, subcutaneous tissue, etc.—suggests that any change in the body that results in the efflux of brain K+ into the bloodstream may impart a change in the K composition of the blood, most likely in the sera/plasma fraction, 69 , 70 with the latter supported by the fact that signal transferal has previously been demonstrated for K concentrations in human AD subjects, wherein a decrease in brain K was associated with a measurable increase in serum K. 3 …”

“… 78 (Note: preprint data also exist in Higgins et al. 79 ) Therefore, the potential of K stable isotopes in the study of mammalian (e.g. human) health and disease remains to be fully assessed, and this can only be done through targeted research.…”