Using ¹H₂O MR to measure and map sodium pump activity in vivo

The cell plasma membrane Na⁺,K⁺-ATPase [NKA] is one of biology's most [if not the most] significant enzymes. By actively transporting Na⁺ out [and K⁺ in], it maintains the vital trans-membrane ion concentration gradients and the membrane potential. The forward NKA reaction is shown in the Graphical Abstract [which is elaborated in the text]. Crucially, NKA does not operate in isolation. There are other transporters that conduct K⁺ back out of [II, Graphical Abstract] and Na⁺ back into [III, Graphical Abstract] the cell. Thus, NKA must function continually. Principal routes for ATP replenishment include mitochondrial oxidative phosphorylation, glycolysis, and creatine kinase [CrK] activity. However, it has never been possible to measure, let alone map, this integrated, cellular homeostatic NKA activity in vivo. Active trans-membrane water cycling [AWC] promises a way to do this with ¹H₂O MR. In the Graphical Abstract, the AWC system is characterized by active contributions to the unidirectional rate constants for steady-state water efflux and influx, respectively, k_io(a) and k_oi(a). The discovery, validation, and initial exploration of active water cycling are reviewed here. Promising applications in cancer, cardiological, and neurological MRI are covered. This initial work employed paramagnetic Gd(III) chelate contrast agents [CAs]. However, the significant problems associated with in vivo CA use are also reviewed. A new analysis of water diffusion-weighted MRI [DWI] is presented. Preliminary results suggest a non-invasive way to measure the cell number density [ρ (cells/μL)], the mean cell volume [V (pL)], and the cellular NKA metabolic rate [^cMR_NKA (fmol(ATP)/s/cell)] with high spatial resolution. These crucial cell biology properties have not before been accessible in vivo. Furthermore, initial findings indicate their absolute values can be determined.