Re-examining the Classical Hypothesis of the S4 Voltage-Sensor in Potassium Channels

Re-examining the Classical Hypothesis of the S4 Voltage-Sensor in Potassium Channels

Sun Zuodong

The gating regulatory mechanism of voltage-gated potassium channels constitutes a fundamental core issue in cellular electrophysiology and neurobiology. Since the resolution of channel crystal structures, a well-entrenched view has prevailed in academia: the S4 transmembrane segment of the channel is rich in positively-charged amino-acid residues. It is thought to specifically sense changes in membrane potential and trigger channel opening via conformational sliding and charge displacement, and is thus defined as the exclusive voltage sensor of voltage-gated channels. This hypothesis has been in use for decades and has largely dominated mainstream frameworks for interpreting ion-channel mechanisms, designing experiments, and constructing models.

Re-evaluated in light of the new dynamic Potassium Channel Origami Windmill Tetramer Model, the traditional S4 voltage-sensor theory leaves considerable room for debate with respect to causal logic, dynamic interpretation and underlying physical mechanisms.

First and foremost, the classical theory suffers from a core confusion between correlation and causation. Existing structural-biological observations only confirm that slight conformational shifts and lateral displacements of the S4 segment occur concomitantly with membrane-potential fluctuations; these are synchronous accompanying phenomena. Nevertheless, previous studies have directly interpreted these correlated structural alterations as the source of functional driving force, presupposing that “S4 acts as an active voltage-sensing element”. For a long time, the research community has overlooked a more fundamental physical mechanism: transmembrane potential differences alter the charge density of potassium ions inside and outside the pore. Accumulation of abundant positive charges generates strong like-charge electrostatic repulsion, exerting structural thrust upon the overall four-subunit assembly. This provides fully plausible physical conditions for driving channel conformational changes. Accordingly, S4 displacement is more likely to be a consequence rather than the initiating cause of gating regulation.

Second, static crystal structures cannot faithfully recapitulate dynamic physiological processes. Derived from frozen static structures, the classical sliding model infers dynamic gating behaviour from discrete segmental sliding to account for continuous, reversible, finely tunable bioelectrical activity — which inherently creates a mechanistic disconnect. By contrast, the origami windmill dynamic model centres on coordinated rotation of four subunits driven by electrostatic repulsion, with pore aperture modulated by rotational speed. Without postulating a dedicated sensor, it offers a self-consistent account of the full dynamic sequence including channel opening, closure, fine-tuning and repolarisation, and better conforms to real-world physiological behaviour.

Third, functional relationships are reinterpreted from fundamental physical logic: ion-channel gating is essentially charge-force-dominated structural motion instead of active sensing behaviour of protein segments. Membrane potential merely serves as an external condition that modulates ion accumulation density and repulsion magnitude. The actual motive force for channel opening and closing stems from the electrostatic interactions of potassium ions themselves. Within this framework, S4 conformational changes represent secondary structural variations arising during the windmill-like collective rotation of the four-blade subunits. S4 does not possess the core capacity for independent voltage sensing or autonomous gating initiation.

This paper adheres to rigorous academic debate principles: it does not reject all previously obtained structural-observation experimental data, but only revises long-standing misattributions of causal relationships and biases in functional assignment. The decades-long entrenchment of the S4-sensor theory does not stem from erroneous experimental facts. Instead, it arises from a narrow interpretive paradigm and highly convergent lines of thinking, whereby mechanistic understanding has long remained at the superficial structural level and failed to reach the underlying essence of electrostatic-force-driven processes.

In summary, available evidence is insufficient to support the definitive conclusion that “S4 functions as the exclusive voltage sensor”. Compared with the conventional hypothesis, the alternative explanatory system — in which electrostatic repulsion of potassium ions drives tetramer windmill rotation to govern channel gating — is more parsimonious, internally consistent and aligned with fundamental physical laws.

This proposition is fully falsifiable and reproducible. Its validity can be further tested through dynamic structural simulations, electrophysiological control experiments and site-directed mutagenesis assays. It is offered for prudent academic discussion, objective re-examination and dialectical refinement of the fundamental theoretical framework for ion-channel gating.