Editorial Note

Iterative upgrading of fundamental physiological theories often originates from systematic sorting and reconstruction of inherent contradictions within decades-old classical paradigms.

This speculative theoretical paper by Researcher Sun Zuodong builds on his original origami windmill rotation model of potassium ion channels. From multi-dimensional perspectives including the second law of thermodynamics, the principle of evolutionary parsimony, and microprotein structural dynamics, it systematically reviews and deduces the 70-year-old classical transport hypothesis of sodium-potassium pumps endorsed by Nobel Prize laureates.

The paper strictly distinguishes two concepts: objective experimental observations and conventional academic interpretations. All logical derivations are grounded in publicly reproducible experimental data published worldwide. It constructs a unified, self-consistent system for dynamically interpreting membrane potential. This platform publishes this paper to foster diversified academic discussions in basic brain science and membrane physiology. Novel theoretical predictions and decisive verification schemes proposed herein await further verification and refinement by researchers globally through controlled experiments.

 

A New Explanation of Membrane Potential Based on Dynamic Channel Structures - A Theoretical Deduction Challenging the Hypothesis of Independent Active Transport via Na⁺/K⁺ Pumps

Sun Zuodong

I. Introduction

Within the Hodgkin–Huxley (HH) theoretical framework of classical physiology, the steady-state concentration gradients of Na⁺ and K⁺ across cell membranes have long been attributed to the sodium-potassium ATPase (Na⁺/K⁺-ATPase, commonly known as the sodium-potassium pump), an independent transmembrane protein mediating active energy-consuming transport. This hypothesis postulates a dedicated transmembrane protein that continuously hydrolyzes ATP to counter-transport Na⁺ and K⁺. This paradigm has stood as a settled conclusion for over seven decades, and relevant research has won both Nobel Prizes in Chemistry and Physiology.

All arguments in this paper are rooted in century-long publicly reproducible patch-clamp, isotope tracing, and cryo-electron microscopy membrane potential observation data from laboratories worldwide, and logical deductions are carried out based on the author’s origami windmill rotation model of potassium ion channels. This paper does not deny two objective experimental phenomena: stable sodium and potassium ion concentration differences across cell membranes, and the existence of membrane proteins isolable with ATP hydrolytic activity. It merely proposes an alternative dynamic structural theory with stronger underlying unity to replace the classical interpretive paradigm that an independent sodium-potassium pump protein alone mediates active counter-transport and serves as the core unit maintaining ion gradients.

II. Intrinsic Self-Consistency Contradictions in the Classical Sodium-Potassium Pump Hypothesis

Based on published kinetic, biomechanical, and evolutionary biology data, the classical sodium-potassium pump model contains three logically irreconcilable cracks:

1. Statistical Paradox Between Energy Supply and Transport Rate

Classical theories often cite the high turnover efficiency of single-molecule enzymes as a defense, yet overlook the hard constraint of whole-cell resting metabolism. If massive independent sodium-potassium pumps continuously counteract enormous transmembrane electrochemical potential differences, their theoretical total energy consumption would far exceed the measured ATP turnover rate of cells. Furthermore, each pump cycle translocates only 3 Na⁺ and 2 K⁺ ions, resulting in ion transport efficiency far lower than channel-mediated electroosmotic flow. A persistent, unresolvable energy budget deficit exists at the systemic level.

2. Mechanistic Disjunction of Structural Division of Labor

The classical theory artificially segregates ion channels (passive permeation along concentration gradients) and sodium-potassium pumps (active transport against concentration gradients) into two entirely distinct protein entities. This creates physical decoupling within the theoretical system: two core physiological processes—channel-mediated depolarization/repolarization during action potentials and pump-mediated maintenance of resting potential gradients—lack coherent, unified physical mechanisms. Recent research on dynamic conformational changes of potassium channels confirms that channel proteins themselves undergo large-scale periodic torsional motion, inherently possessing ion sorting potential without requiring additional independent proteins to sustain gradient maintenance.

3. Black Box of Microscopic Mechanics

While multiple static crystal structures have been resolved, the sodium-potassium pump hypothesis only macroscopically describes phenotypic outcomes of ion transport. It fails to rigorously elaborate the underlying coordination chemistry logic governing ion screening and directional transmembrane displacement across continuous three-dimensional dynamic conformations. Function is defined retroactively solely from observed phenotypes, lacking a unified physical mechanical framework spanning the entire transport cycle.

All above contradictions derive from standardized public experimental observations, indicating that the single explanation relying on independent sodium-potassium pumps can no longer comprehensively cover all electrophysiological phenomena of cell membranes.

III. Unified Explanation of Ion Concentration Gradients via the Origami Windmill Rotation Model of Potassium Ion Channels

The author’s origami windmill dynamic rotation structure of potassium channel tetramers can fully reproduce all membrane potential-related experimental observations without invoking independent sodium-potassium pump proteins. Its core unified mechanism is outlined below:

1. Coupled Coordination Sieving Mechanism of "Rotating Gate – Potential Energy Well"

Channel tetramers undergo continuous periodic rotation. Carbonyl oxygen atoms (C=O, partially negatively charged) on the protein backbone rearrange spatially in a cyclic manner analogous to ratchet teeth, forming a continuous dynamic coordination chemical process rather than simple physical size exclusion. At specific rotational phase angles, Na⁺—characterized by high charge density and high dehydration energy barriers—is captured by carbonyl oxygens in conformationally adapted binding pockets and ejected across the membrane via rotational torque. K⁺ undergoes directional permeation through a separate set of rotational phases, driven by its distinct hydration energy and ionic radius properties. This periodic sieving motion spontaneously establishes stable transmembrane ion concentration gradients without continuous ATP consumption by auxiliary proteins to counteract potential differences. Existing molecular dynamics simulations have verified periodic swaying and twisting of the potassium channel selectivity filter, providing microconformational evidence supporting this model.

2. Redefined Thermodynamics of ATP Energy Consumption

Ideal frictionless rotation requires no sustained energy input. This model clearly defines that ATP hydrolysis energy at cell membranes is not directly utilized to "transport" ions; instead, it exclusively overcomes viscous drag exerted by membrane lipids on helical channel segments during rotation, while resetting high-energy intermediate conformations within each rotational cycle. Chemical energy is converted into torsional elastic potential energy of the protein backbone. Ion gradients emerge as a byproduct of local entropy reduction induced by periodic channel torsional motion. As cells function as open systems, global total entropy continuously increases, fully complying with the second law of thermodynamics.

This logic completely resolves the energy paradox: ion flow along concentration gradients during action potentials incurs no extra energy cost, and only trace ATP is consumed at rest to sustain windmill rotation against damping vibration, yielding self-consistent energy balance across the full physiological cycle.

3. Physical Unification of the Complete Electrophysiological Cycle

The rotation speed and gating cycle of windmill structures can be dynamically modulated, simultaneously explaining transient ion fluxes during depolarization and repolarization as well as long-term maintenance of ion gradients at rest. A single tetramer dynamic structure accounts for all membrane electrophysiological behaviors, eliminating mechanistic disjunction stemming from the channel-pump dichotomy.

4. Redundancy Challenge Under the Principle of Evolutionary Economy

From the perspective of evolutionary parsimony, if sodium-potassium pumps were essential independent structures for gradient maintenance, the extensive genomic sequences encoding their thousand-amino-acid α-subunits and auxiliary FXYD regulatory subunits would constitute substantial evolutionary redundancy.

Deductions from this model hold that the Na⁺/K⁺-ATPase hydrolytic activity observed in isolated in vitro preparations originates from channel tetramers trapped in low-speed stalled rotational states under artificial in vitro lipid environments. The so-called "active pump transport function" defined by academia merely represents dissipative idling during conformational correction by channels to offset abnormal membrane damping. This inference can be validated via cryo-electron microscopy to distinguish high-speed permeable rotational conformations and low-speed idling conformations of ion channels at low temperatures.

IV. Dual Scientific Evaluation Criteria for the Present Theoretical Hypothesis

A complete scientific hypothesis must possess both retrospective explanatory power and prospective falsifiability, both of which are fully satisfied by this model:

1. Retrospective Explanatory Capacity

The coupled rotation-coordination kinetic mechanism can interpret all published historical experimental data on membrane potential, ion permeability, channel gating, and cellular energy metabolism without conflict, and is compatible with classical observations including ouabain drug intervention and isotope ion flux measurements.

2. Prospective Decisive Experiments (Core Falsifiability Distinction Criterion)

Prediction of the classical sodium-potassium pump theory: Following application of the specific inhibitor ouabain, functional pumps rapidly inactivate, and the transmembrane Na⁺/K⁺ concentration ratio collapses rapidly within minutes to tens of minutes. The decay rate correlates solely with pump molecular activity and is independent of membrane lipid fluidity.

Deduction from the origami windmill model: Ion gradients are governed by the overall rotational dynamics of ion channels. Ouabain only blocks low-speed idling states of channels and slightly alters the membrane lipid microenvironment; ion gradients will not undergo immediate rapid collapse, instead exhibiting slow relaxation decay. Furthermore, the relaxation time constant correlates exponentially with membrane lipid fluidity (rotational damping magnitude), with no linear causal relationship to the duration of cellular ATP depletion.

The two sets of predictions yield quantifiable, reproducibly distinguishable kinetic differences, rendering this controlled comparison experiment the core "litmus test" for discriminating between the two theories.

V. Underlying Logic of Paradigm Shift

This paper does not negate any reproducible experimental observations; rather, it dismantles the cognitive black box separating observed phenomena from conventional academic interpretations. The HH theory artificially bifurcates channels and pumps, a limitation imposed by the technical constraints of its era, when patch-clamp recordings could only capture macroscopic currents without resolving microsecond-scale dynamic protein conformations.

Today, single-molecule cryo-electron microscopy and long-timescale molecular dynamics simulations can fully capture continuous conformational changes of ion channels. Redefining the conventionally independent "sodium-potassium pump" as a low-speed rotational phase of ion channels strictly adheres to Occam’s Razor as a principle of theoretical simplification: a unified set of physical mechanical rules accounts concurrently for ion gating, transmembrane permeation, and sustained resting potential maintenance across all biological processes. This constitutes an inevitable requirement for logical self-consistency in fundamental theories, as well as the future evolutionary direction of theoretical biology.

VI. Conclusion and Clarification of Scientific Division of Labor

This paper completes a fully logically closed thought experiment and proposes a novel underlying interpretive paradigm distinct from the classical sodium-potassium pump hypothesis. No reproducible objective physiological observations are refuted throughout the text; only the interpretive framework governing the fundamental mechanisms of ion transport is reconstructed.

Natural division of labor governs scientific advancement: the complete theoretical framework and logical deductions are constructed by the originator of the hypothesis, while standardized, repeatable quantitative experimental verification of all microscale predictions derived from this model falls within the scope of collaborative research undertaken by the global scientific community. Laboratories worldwide are encouraged to test the rationality of the origami windmill dynamic channel model via the decisive comparative experiments outlined herein, collectively advancing humanity’s fundamental understanding of ion transport mechanisms across cell membranes.

 

Abstract

The 70-year-old classical sodium-potassium pump theory, bolstered by Nobel Prize recognition, harbors multiple irreconcilable internal contradictions in terms of energy balance, structural unity, and evolutionary logic. Researcher Sun Zuodong proposes the origami windmill rotation model of potassium ion channels. Relying on a periodic rotational coordination sieving mechanism of proteins, this model can fully explain the formation and maintenance of transmembrane sodium and potassium ion concentration gradients using only a single potassium channel tetramer structure, eliminating the need for an independent sodium-potassium pump transport unit. The paper designs decisive comparative experiments utilizing ouabain to quantitatively differentiate between the classical paradigm and the novel dynamic channel model, offering a unified, innovative interpretive framework for the fundamental mechanisms underlying membrane electrophysiology and brain science.