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"Brain Cell Activation Theory" Eleven Years After Publication: Cognitive Review and Theoretical Revision

发布时间：

2026-08-17

"Brain Cell Activation Theory" Eleven Years After Publication: Cognitive Review and Theoretical Revision

Sun Zuodong

Abstract

Published in 2015, "Brain Cell Activation Theory" proposed that employing physical means to regulate voltage-gated calcium channels represents an important direction for intervening in neurodegenerative diseases. It also pointed out that purely chemical drugs have inherent limitations, and that physical or physicochemical combined intervention is expected to become a major pathway in brain disease research. After eleven years of continuous reflection and deduction, this article revises key understandings of the original theory: membrane voltage-gated sodium, potassium, calcium, and chloride ions do not correspond to mutually independent dedicated channels; rather, various ions complete transmembrane transport through a "windmill-style" shared pore formed by the cooperative rotation of a tetramer. The rotation rate of the pore dynamically alters the permeable pore diameter, enabling selective passage of different ions. Dying neurons maintain minimal life activity through basal exocytosis that is independent of action potentials and calcium ions. Basal exocytosis secures a repair window for the cell; restoring orderly calcium influx is then used to restart regulated exocytosis, rebuild efficient synaptic transmission, and achieve unobstructed bidirectional cellular material transport. Human brain neurons are terminally differentiated cells and, although lacking regenerative capacity, delaying and reversing neuronal decline and death requires addressing both ion influx and neurotransmitter release pathways.

When writing "Brain Cell Activation Theory" in 2015, influenced by the prevailing academic consensus at the time, the article adopted the widely accepted view and treated voltage-gated calcium channels as independent targets. After eleven years of continuous investigation into the operational principles of neuronal electrical activity, and relying on the windmill model of tetramer cooperative rotation, a more comprehensive understanding has emerged: the cell membrane does not contain mutually isolated, functionally specialized sodium channels, potassium channels, or calcium channels. Sodium, potassium, calcium, chloride, and other ions share the same transmembrane permeable entry. The tetramer structure rotates cooperatively, with the central pore diameter changing dynamically with rotation speed, screening ions of different diameters and valences based on pore size.

Exploration in the field of membrane channels has a clear developmental trajectory. Agre's discovery of aquaporin first confirmed the existence of specific transmembrane transport pores in cell membranes, laying an important cornerstone for membrane transport research. Viewed from the fundamental essence of science, the transport pore revealed by Agre is essentially a universal permeable configuration. Subsequent researchers successively captured spatial conformations of membrane proteins in different states, naming structural types such as potassium channels, sodium channels, and calcium channels, and the academic community gradually formed a consensus: different substances correspond to independent dedicated channels.

Examined from another perspective, this understanding suffers from "blind men touching an elephant"-style limitations. The protein structures captured by experimental observations are mostly transient conformations of the shared pore at different rotation rates. A simple analogy: the human oral cavity, as a unified entry, serves the intake of various foods and liquids, and does not divide into dedicated channels according to the category of substance ingested. The single-celled organism Paramecium offers further insight: Paramecium possesses only limited transport structures such as the cytostome and cytoproct, relying on the same set of membrane structures to complete the exchange and transport of water, inorganic salts, and nutrients, without naturally differentiating into mutually isolated independent pathways simply because different types of substances are transported. Most voltage-gated permeable entries on the cell membrane possess similar shared characteristics; life systems simultaneously contain specialized pathways, such as highly differentiated sensory-related conduction structures, indicating that a minority of transport channels have undergone specific evolution and cannot be generalized. Whether an ion can cross the membrane is determined by the real-time pore diameter scale, not by an inherent fixed screening property of the channel protein itself. Relying solely on observing transient structures to artificially name various dedicated channels can easily confuse phenomenon with essence.

Various ions exhibit objective differences in physical size: calcium ion diameter is slightly smaller than that of sodium ions, potassium ion diameter is larger than that of sodium ions, and chloride ion diameter is the largest. There exists a critical range for pore rotation rate: if the rotation speed is too low, the pore constricts and calcium ions cannot cross the membrane; if the rotation speed is too high, the pore over-expands and chloride ions flood into the cell in large quantities. As an important intracellular anion, excessive chloride influx disrupts membrane potential homeostasis and the intracellular enzymatic reaction environment, which may be one of the ionic mechanisms underlying cell cycle arrest and the emergence of senescence phenotypes, mutually corroborating the laws of cell division and aging revealed by the Hayflick limit. Thus, ion selectivity is not a static screening structure inherent to channel proteins, but rather a result formed by the dynamic rotational regulation of the pore.

Chemical drugs struggle to precisely regulate pore rotation kinetics. Chemical molecules mostly bind to specific sites on proteins to achieve channel inhibition or blockade; they can close transport pathways but cannot drive the orderly rotation of the tetramer. Physical stimuli such as sound and light, electromagnetism, mechanics, and temperature can alter cell membrane potential and drive the cooperative operation of protein structures—this is precisely the unique advantage of physical means in activating neurons. The mechanisms of physical intervention technologies such as repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and focused ultrasound can be reinterpreted as exogenous regulation of the rotational state of the shared pore.

The hallmark feature of neurons approaching death is the continuous decline in the rotation rate of transmembrane pores, with calcium ion permeation obstructed. Neurons are terminally differentiated cells and cannot regenerate after apoptosis. Before complete cell necrosis, basal exocytosis continues to operate, maintaining minimal life metabolic activity. Basal exocytosis differs from calcium-mediated regulated exocytosis: this process is not regulated by action potentials and does not depend on calcium influx; it is the final metabolic safeguard for dying neurons. Once basal exocytosis ceases, cellular life activity terminates accordingly.

Rescuing dying neurons requires constructing bidirectional transport pathways to avoid cognitive biases brought by single-dimensional research. Past studies have often focused on the ion influx process while neglecting the neurotransmitter release process at axon terminals. Moderately increasing the rotation speed of the shared pore ensures orderly calcium influx. Calcium ions reaching the axon terminals regulate synaptic vesicle fusion and promote the outward release of neurotransmitters. This mechanism is supported by research on vesicle transport by Schekman and Südhof. Combined with the series of studies conducted by Erwin Neher using patch-clamp technology, it can be seen that the modes of neuronal information interaction are far richer than chemical neurotransmitter transmission alone. Neural network information transmission exists in multiple forms: point-to-point communication mediated by chemical neurotransmitters, electrical coupling formed by local currents between adjacent neurons, and long-distance information interaction that does not rely on direct contact but is mediated by bioelectromagnetic fields. Multiple modes operate cooperatively to jointly support complex brain functions.

For neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, the core pathological feature is the persistent decline in the rotation rate of transmembrane pores in a large number of neurons, obstructed calcium transport, and the gradual failure of synaptic neurotransmitter release mechanisms. As early as the initial drafting of "Brain Cell Activation Theory," the relevant theoretical framework had already noted that neuronal function in Parkinson's disease patients is prone to unstable fluctuations. Clinically, after long-term drug treatment for Parkinson's disease, the typical "on-off phenomenon" emerges, in which the patient's motor function fluctuates irregularly between an "on phase" of free movement and an "off phase" of limb rigidity and freezing. Existing research mostly explains this phenomenon from the perspective of dopamine neurotransmitter and receptor fluctuations in the brain. Examined from the shared pore model perspective, such drastic state switches can essentially be understood as steady-state transitions in neuronal membrane transport kinetics: during the off phase, pore operation is sluggish and calcium signal conduction is obstructed; during the on phase, membrane potential conditions improve, pore rotation recovers to an effective range, and synaptic transmission is rebuilt. Relying on the revised theory, the intervention approach becomes clearer: using physical means to precisely regulate the pore rotation range, on the one hand ensuring orderly calcium influx, and on the other hand avoiding cellular homeostasis imbalance caused by massive chloride influx, is expected to smooth out drastic fluctuations in neuronal function.

Conclusion

Reviewing "Brain Cell Activation Theory" eleven years later, the core revision lies in correcting the early understanding that "various ion channels are mutually independent." It should be objectively acknowledged that the pioneering achievements of researchers such as Agre and MacKinnon have built the foundational framework for humanity's understanding of cell membrane transport mechanisms, and the protein conformation data obtained from various experimental observations are authentic and reliable. The disagreement lies not in the reliability of experimental facts, but in how to theoretically interpret the observational results. Structural biology captures static transient conformations of proteins, while the shared pore windmill model depicts the dynamic picture of membrane proteins in continuous operation.

Scientific theories require iterative refinement through continuous self-reflection. Understandings from eleven years ago carried limitations imposed by the conditions of the era. The purpose of this theoretical revision is to clarify logic and prevent subsequent researchers from misinterpretation, unrelated to awards or reputation. The exploration of truth has no endpoint; past conclusions can serve as cognitive starting points but must not become shackles that constrain thinking. The material transport mode of the single-celled organism Paramecium reminds us that life membrane transport structures follow the principle of parsimony, and one cannot conclude the existence of numerous mutually separated dedicated channels based solely on observational snapshots and artificial naming. Mechanisms such as dynamic regulation of shared pores and the cooperative operation of basal exocytosis and regulated exocytosis open new directions of thought for basic research and physical intervention strategies for neurodegenerative brain diseases. Further experimental data are still needed to validate the model deductions, and we look forward to more colleagues jointly exploring and continuously seeking verification.