Structure and mechanism of cellular cation-transporters: Affinity-binding and murburn models

The classical membrane pump theory (CMPT) is an acclaimed hypothesis in cellular electrophysiology, which solicits the functioning of high-affinity/selective electrogenic and size-based pumping/channeling of cations by membrane-embedded proteins. Herein, we analyze the structure-function correlations of Na⁺/K⁺ ATPase and potassium channels (like KcsA) and make a point-wise comparison of several facts/facets of the electrophysiological system, to demonstrate that murburn model fares better than CMPT for explaining the homeostatic electrophysiology mediated by these proteins. We also analyze the foundational progression and principles of cation-centric CMPT from historical (assumptions, deductions, individuals, etc.), mathematical, chemico-physical, evolutionary, and experimental perspectives; and find it unviable at multiple quarters. Thereafter, building upon our earlier publications, we question the acclaimed Goldman-Hodgkin-Katz relation (GHK, an integral part of CMPT), which is based on the membrane-permeability of the major cations (≥10^-1 M Na⁺/K⁺), and which supposedly accounts for the resting trans-membrane potential (TMP) observed in diverse cells. Finally, we present the murburn-based explanation for cellular/organellar TMP, which rests on small amounts of spontaneously formed anionic diffusible reactive species (ADRS, like superoxide anion formed from oxygen; present inside at ≤10^-6 M) within the reducing microenvironment, aided by murzymes. The oxygen-centric murburn view of electrophysiology is: (i) thermodynamically and kinetically facile, (ii) agrees with structure-function aspects of the components, particularly membrane proteins, (iii) colloidal nature of the cytoplasm, (iv) explains salient observations in the field, (v) reasons out hitherto inexplicable conundrums like the critical need for oxygen, and (vi) has the ability to explain the impact of simple or complex inhibitors/modulators.