Na,K‐ATPase: A murzyme facilitating thermodynamic equilibriums at the membrane‐interface

Abstract

The redox metabolic paradigm of murburn concept advocates that diffusible reactive species (DRS, particularly oxygen-centric radicals) are mainstays of physiology, and not mere pathological manifestations. The murburn purview of cellular function also integrates the essential principles of bioenergetics, thermogenesis, homeostasis, electrophysiology, and coherence. In this context, any enzyme that generates/ modulates/utilizes/sustains DRS functionality is called a murzyme. We have demonstrated that several water-soluble (peroxidases, lactate dehydrogenase, hemogoblin, etc.) and membrane-embedded (Complexes I-V in mitochondria, Photosystems I/II in chloroplasts, rhodopsin/transducin in rod cells, etc.) proteins serve as murzymes. The membrane protein of Na,K-ATPase (NKA, also known as sodium-potassium pump) is the focus of this article, owing to its centrality in neurocardio-musculo electrophysiology. Herein, via a series of critical queries starting from the geometric/spatio-temporal considerations of diffusion/mass transfer of solutes in cells to an update on structural/distributional features of NKA in diverse cellular systems, and from various mechanistic aspects of ion-transport (thermodynamics, osmoregulation, evolutionary dictates, etc.) to assays/explanations of inhibitory principles like cardiotonic steroids (CTS), we first highlight some unresolved problems in the field. Thereafter, we propose and apply a minimalist murburn model of trans-membrane ion-differentiation by NKA to address the physiological inhibitory effects of trans-dermal peptide, lithium ion, volatile anesthetics, confirmed interfacial DRS + proton modulators like nitrophenolics and unsaturated fatty acid, and the diverse classes of molecules like CTS, arginine, oximes, etc. These explanations find a pan-systemic connectivity with the inhibitions/uncouplings of other membrane proteins in cells.

Synthesis of theories on cellular powering, coherence, homeostasis and electro-mechanics: Murburn concept & evolutionary perspectives

“…As per the Murburn model (Manoj et al, 2016a;Parashar & Manoj, 2022), the cell functions as a simple chemical engine (SCE) and the redox proteins serving as generators, modulators, sustainers and utilizers of DRS enable it to work in this capacity (Manoj et al al., 2022h). Since the generic format of the interaction of DRS with the substrate is core of xenobiotic metabolism, it obviates the need for protein-inducibility and topology complementation between enzyme active site and xenobiotic.…”

“…The murburn models for ATP synthesis by hemoglobin provides a viable explanation for powering and for ion-differentiation by Na,K-ATPase and by cytosolic Na + excluding and K + accumulating proteins like actin (Manoj et al, 2022h). It is a tangible means to explain RBC's ability to enable bulk ATP-synthesis and maintain its cellular electrophysiological features.…”

“…Here, it is opportune to point out that water in cells must not be seen as ordinary water but must be seen as a discretized and heterogenous phase, with rather fixed and mobile formats. Manoj et al, 2022h for more details.) A simple fuel (like methane) can be burned or murburned in a simple chemical engine or cell (respectively) to produce water and carbon dioxide, liberating heat.…”

“…This simplistic perception is definitely outdated now because the coacervate nature of cytoplasm is a non-questionable direct observation. Also, the proposal of deterministic ion-pumping has been demonstrated to be a thermodynamically untenable proposal (Manoj et al, 2022h). Therefore, the cell theory (which stressed overt importance on the membrane alone) must be expanded to accommodate coacervation, so that the internal phases also get their due importance.…”

“…Figure 6: A simplified rendition of the murburn SCE (Simple Chemical Engine) model of cell function, which depends on Effective Charge Separation (ECS) for cellular powering, thermogenesis, homeostasis, coherence, electrical activity, mobility, etc. (Please referManoj et al, 2022h for more details.) A simple fuel (like methane) can be burned or murburned in a simple chemical engine or cell (respectively) to produce water and carbon dioxide, liberating heat.…”