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 Table of Contents  
REVIEW
Year : 2022  |  Volume : 1  |  Issue : 4  |  Page : 155-165

Role of microtubules in neuro-electrical transmission: a hypothesis


School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong Province, China

Date of Submission18-Oct-2022
Date of Decision10-Dec-2022
Date of Acceptance23-Dec-2022
Date of Web Publication30-Dec-2022

Correspondence Address:
Bao Ting Zhu
School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong Province,
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2773-2398.365025

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  Abstract 

Unlike man-made electronic devices such as computers, the nervous system never suffers from “overheating” due to its massive neuro-electrical activities. This paper proposes a new hypothesis that neuronal microtubules (neuro-MTs), which are major structural components of axons and dendrites, are vacuum cylindrical nanotubes that can mediate electrical transmission with a unique form of quasi-superconductivity. It is speculated that hydrolysis of guanosine triphosphate catalyzed by the a-/ß-tubulin subunits would supply cellular energy to relocate electrons to form the conduction electrons inside neuro-MTs. Owing to the consecutive dipole ring structures of neuro-MTs, the moving speed of the conduction electrons inside neuro-MTs is expected to be very slow, and this feature would enable physiological neuro-electrical transmission with super-high energy efficiency. Further, the dipole ring structures of a neuro-MT would help terminate the electron conduction with high efficiency. The proposed neuro-MT-mediated electrical transmission offers a new mechanistic explanation for the saltatory conduction of action potentials along the axons. Lastly, it is speculated that owing to its unique consecutive dipole sheet structures, the myelin sheath which wraps around large axons and some dendrites, may functionally serve as an effective shield for the electromagnetic fields generated by the conduction electrons inside the axonal neuro-MTs.

Keywords: neuro-electrical transmission; neuronal microtubules; quasi-superconductivity; saltatory conduction; tubulin


How to cite this article:
Zhu BT. Role of microtubules in neuro-electrical transmission: a hypothesis. Brain Netw Modulation 2022;1:155-65

How to cite this URL:
Zhu BT. Role of microtubules in neuro-electrical transmission: a hypothesis. Brain Netw Modulation [serial online] 2022 [cited 2023 Jan 30];1:155-65. Available from: http://www.bnmjournal.com/text.asp?2022/1/4/155/365025


  Introduction Top


The nervous system, the brain in particular, has massive neuroelectrical activities occurring almost all the time, even during sleep. Unlike man-made electronic devices such as computers, the nervous system surprisingly never suffers from “overheating” due to its overwhelming amount of neuro-electrical transmission. It is speculated that the neuro-electrical transmission in the nervous system likely is mediated by a unique form of quasi-superconductivity which takes place under physiological and room temperature conditions.

At present, the Bardeen-Cooper-Schrieffer theory (Bardeen et al., 1957) has been widely accepted to explain the mechanism of superconductivity of regular metallic or composite superconductors. The theory posits that the spin-paired pairs of conduction electrons (commonly referred to as the Cooper pairs) are formed in the metal conduction band. One of the electrons in the Cooper pair may electrically distort the molecular structure of the superconducting material as it moves through, creating nearby a short-lived concentration of positive charge. The other electron in the pair may then be attracted toward this positive charge. It has been suggested that such coordination between electrons can prevent them from colliding with composite molecules of the conductor and thus eliminate electrical resistance. Based on this theory, when temperature decreases, the number of Cooper pairs would, in principle, increase, and ultimately the superconductor becomes a fully spin-paired, diamagnetic system. The theory helps to explain the lower temperature superconductors, but fails to satisfactorily explain the high-temperature superconductors.

In a recent paper, a new hypothesis concerning a physical requirement of the superconducting material is proposed, and the inclusion of this hypothetical element helps better explain the phenomenon of superconductivity on the basis of the existing Bardeen-Cooper-Schrieffer theory (Zhu, 2022). It is suggested that for superconductivity (i.e., with zero resistivity) to occur, the conductor must have nano-sized straight vacuum tunnels inside with radius size large enough to allow the passage of conduction electrons in a ballistic manner without collisions. In addition, some of the composite atoms of the conductor should be able to readily release electrons to form the conduction band. This hypothesis is supported by experimental observations in the literature, and also offers a plausible explanation for why carbon nanotubes or graphene sheets can become superconducting under certain conditions as these nano-devices contain ample vacuum spaces inside their structures for collision-free passage of the conduction electrons (Zhu, 2022). Based on the new explanation on superconductivity tendered above (Zhu, 2022), it naturally leads to the suggestion that the neuro-MTs, which are major structural components of axons and dendrites, may function as unique nano-sized bio-devices that can mediate electrical transmission with a quasi-superconducting property. Provided below is a detailed explanation of the proposed hypothesis along with a discussion of the potential supporting evidence which is scattered in the literature in bits and pieces.


  Neuro-Microtubules May Mediate Neuro-Electrical Transmission Top


Microtubules (MTs) are ubiquitously present in eukaryotes. In non-neuronal cells, MTs are important components of the cytoskeleton, involved in many cellular functions, such as material transport, cell motility, and cell division (Nogales, 2000; Gudimchuk and McIntosh, 2021). In neuronal cells, MTs also help to fulfill the important function of axonal transport of organelles (Grafstein and Forman, 1980; Vallee and Bloom, 1991; Hollenbeck and Saxton, 2005).

Structurally, MTs are linear cylindrical tubes made of tubulin polymers, with the outer and inner diameters of approximately 25 and 14 nm, respectively (Li et al., 2002). Tubulin is approximately 8 nm × 5 nm × 4 nm in size (with a molecular weight of 110 kDa) and consists of α-and β-tubulin subunits (Nogales et al., 1998; Löwe et al., 2001; Li et al., 2002). Structurally, each MT usually consists of 13 rows of protofilaments (Tilney et al., 1973) made of α-/β-tubulin heterodimers, and the protofilaments are associated laterally and closed into a nanotube (Unger et al., 1990; Nogales et al., 1999; Portet et al., 2005). MTs consisting of a larger or smaller number of protofilaments are also possible (Unger et al., 1990; Portet et al., 2005), which may affect the lattice structure and stability. There are two types of MT lattice structure: one type has the rotational symmetry, and the whole tube is continuous without a seam in which α-subunits are next to α-subunits (α–α) and β-subunits next to β-subunits (β–β) [Figure 1]A. Another lattice structure has a physical discontinuity known as a seam, where the α-subunits in a protofilament associate laterally with β-subunits in the adjacent protofilament (α–β) (Li et al., 2002; Craddock et al., 2009; Sui and Downing, 2010). It is generally thought that the seam is a weak point in the MT structure (Sui and Downing, 2010).
Figure 1: A neuro-microtubule (MT) inside an axon may mediate neuro-electrical transmission with quasi-superconductivity.
Note: (A) A small fraction of a neuro-MT showing the basic symmetrical cylindrical structure which contains 13–15 filaments made of a-/ß-tubulin heterodimers. It is speculated that the neuro-MT has a continuous ring structure without a visible seam. Each α-/β-tubulin heterodimer unit can form a strong dipole (refer to Figure 2A for more detail). As indicated, for a neuro-MT inside an axon, it has a clear polarity, with the plus end located at the distal end of the axon and the minus end close to the cell body. This polarity of a neuro-MT is exactly opposite in a dendrite. (B) It is hypothesized that the neuro-MT inside an axon has a hollow and vacuum passage inside and can allow collision-free passage of the conduction elections. When an action potential (AP) is initiated, Na+ channels at or near the trigger zone (which is the beginning part of the axon) are activated, resulting in Na+ influx accompanied by a sharp rise in voltage inside that particular segment of the axon and neuro-MT. As a result, free electrons will form the conduction band moving toward the initiating end of a neuro-MT where it has a higher electric potential.


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At present, much less is known about the space inside a MT in terms of content and significance. In non-neuronal cells, electron microscopic analysis of the cross sections of MTs has visualized densities of unknown composition inside (Garvalov et al., 2006). One explanation for these lumenal structures is that they may be enzyme complexes involved in posttranslational modification of tubulin subunits (Soppina et al., 2012). In addition, based on high-resolution structural analysis, it was speculated that the walls of a regular MT in non-neuronal cells might even contain holes that can allow diffusion of water and small molecules such as taxol (Li et al., 2002).

In neuronal cells (in particular in their axons and dendrites), it is hypothesized that most of the MTs are involved in neuroelectrical transmission, and these MTs are referred to as “neuro-MTs.” At present, it is not known whether neuro-MTs can also be used to fulfill other generic cellular functions (such as transportation of cellular cargos). Structurally, it is hypothesized that neuro-MTs will have a hallow and vacuum space inside (depicted in [Figure 1]A), and it is further speculated that neuro-MTs are of the type without a seam, such that it can better help maintain stability as well as vacuum tunnel space inside. Further, it is hypothesized that because of the vacuum space inside neuro-MTs, they can serve as nano-sized bio-devices that mediate neuro-electrical transmission with a unique form of quasi-superconductivity (more explanation is provided later), i.e., it can allow collision-free slow passage of the conduction electrons at all time (depicted in [Figure 1]B).

It is known that the inner part of a nerve fiber or an axon, i.e., its cytosolic compartment, has a negative potential (at approximately -70 mV). The outer surface of neuro-MTs is also negatively charged as the carboxy-terminal tails of α- and β-tubulin subunits contain several acidic residues which are located on the outer surface (reviewed in Roll-Mecak (2015)) [Figure 2]. It is expected that the inner surface of a neuro-MT likely is even more negatively charged according to the distribution of the negatively-charged acidic amino acids in the α- and β-tubulin subunits (Li et al., 2002) [Figure 2]. This structural feature is in agreement with the earlier suggestion that the inner part of the MT may serve as a capacitor for electrons (Satarić et al., 2009; Kalra et al., 2020). Neural stimulation in the form of action potentials occurring at the neural cell membrane (such as at the rigger zone of an axon) will activate Na+ channels, resulting in Na+ influx. The action potential-associated increase in cytoplasmic Na+ at or near a neuro-MT would be functionally similar to applying a higher electric potential to a neuro-MT, which will trigger the release and the conduction of free electrons inside a neuro-MT [Figure 2]B, and the free electrons will move toward where the action potential is initiated [Figure 1]B. Notably, the moving direction of the conduction elections would be opposite to the direction of the electric current, which moves from the neuronal cell body toward the distal end of the axon [Figure 1]B.
Figure 2: Charge distribution along the ring structure made of thirteen α-/ß-tubulin heterodimers.
Note: (A) The red positive charge represents the 18 Ca ions, which are located near the center of each α-/ß-tubulin heterodimer (i.e., at the intra-dimer interfaces), whereas the negative charges are located at the inter-dimer interfaces and are jointly contributed by both α-and β-tubulin subunits. Based on an earlier study, it is estimated that the β-tubulin subunit may contribute nearly twice the amount of negative charges compared to the α-tubulin subunit. (B) Schematic depiction of the charge distribution along the cross-section of a neuro-microtubule (MT) (left panel). When an action potential (AP) is induced, the influx of Na+ would partially neutralize the negative charges on the carboxy-termlnal tail (CTT), which would increase the electric potential in that part of the neuro-MT and result in the formation of free conduction elections in the center of the neuro-MT (shown on the right panel). It should be noted that the positively-charged ring structures and the negatively-charged ring structures are not located on the same cross-sectional plains of a MT; rather they are spaced out by forming the consecutive positivelycharged and negatively-charged “dipole rings” as schematically depicted in Figure 3A.


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Here an important question is: How are the conduction electrons inside neuro-MTs generated? It is known that each α- and β-tubulin subunit has a binding site for guanosine triphosphate (GTP), and the hydrolysis of GTP to guanosine diphosphate is catalyzed by the β-tubulin subunit (Alushin et al., 2014). This enzymatic reaction is estimated to release approximately 10 kcal/mol (i.e., 0.42 eV/molecule) of cellular energy (Scott, 1992). The energy released during GTP hydrolysis can be utilized for the assembly of MTs (Alushin et al., 2014). However, in an already fully-assembled neuro-MT, it is hypothesized that GTP hydrolysis by each α-/β-tubulin heterodimer will help release and relocate electrons that will eventually form the conduction electrons inside the vacuum neuro-MTs (depicted in [Figure 2]A). This idea is somewhat in line with an earlier suggestion that while a negative charge is associated with the α-tubulin subunit before hydrolysis of GTP to guanosine diphosphate, it is relocated to the β-tubulin subunit after hydrolysis (Sataric et al., 1993). It is of note that because of this unique feature, the conduction electrons will always move in the direction from the β-tubulin subunit toward the α-tubulin subunit during neuroelectrical transmission (depicted in [Figure 2]A). This moving direction of the conduction electrons inside neuro-MTs is fully consistent with the so-called “dynamic polarization” of electric signal transmission along axons and dendrites.


  Role of the Consecutive Dipole-Ring Structures of Neuro-Microtubules in Neuro-Electrical Transmission Top


Earlier studies have shown that each α-/β-tubulm heterodimer is an electric dipole with an estimated 18 calcium ions located near the center of the heterodimer (Mershin et al., 2004; Tuszyński et al., 2005) (also depicted in [Figure 2]A). The heterodimer possesses a high overall negative electric charge of approximately 23 e (Mershin et al., 2004; van den Heuvel et al., 2007). Because the carboxy-terminal tails of the tubulin subunits (ranging from 9 to 25 residues in length) have several glutamic acid residues, it is estimated that the subunit may contain over 1/3 of tubulin’s total electrostatic charge, with a net charge of ~12 e (Luchko et al., 2008).

When the carboxy-terminal tails are excluded, the α-/ß-tubulin dimer is estimated to have a dipole moment of 1714–1739 Debyes (Stracke et al., 2002; Mershin et al., 2004; Tuszyński et al., 2005); the magnitude of the dipole moment of α-tubulin is approximately half of that of β-tubulin (Mershin et al., 2004). It was suggested that other factors may affect the tubulin dipole moment in the MT system (Mershin et al., 2004; Tuszyński et al., 2005; Kalra et al., 2020).

Owing to the unique dipole arrangement of the α-/β-tubulin heterodimer (Mershin et al., 2004; Tuszyński et al., 2005), the inner surface of a neuro-MT has consecutive positively-charged and negatively-charged cylindrical structures (depicted in [Figure 3]A). Because of the presence of consecutive dipole ring structures of the neuro-MTs, it is hypothesized that the moving speed of the conduction electrons in each neuro-MT would be far slower than usual, as the two neighboring rings (one positively-charged and one negatively-charged) will each exert a force on the conduction electrons and slow down their passage across each positively-charged ring. Despite the slow conduction speed, it should be noted that the speed by which an electric current is established throughout the entire length of a neuro-MT likely would not be substantially affected by the speed of the conduction electrons, as theoretically it might be similar to the speed of light.
Figure 3: Effect of the consecutive dipole-ring structures on electron conduction inside a neuro-microtubule (MT).
Note: (A) When a conduction electron is right at the center of the positively-charged ring 3, all the forces generated by the neighboring dipole rings 1-5 that act on the electron will be cancelled out. (B) However, when the electron is in between the positively-charged ring 3 and the negatively-charged ring 4 as schematically depicted, the forces generated by the neighboring rings will strongly slow down its conduction through a positively-charged ring to the next positively-charged ring. Note that the length of each arrow is drawn proportional to the exact magnitude of the calculated force. In addition, as soon as the neural stimulation (i.e., the action potential (AP) or electric potential) disappears, the electron conduction will come to a complete stop almost instantaneously without any after-current, and the conduction electrons would be forced to stop exactly where the positively-charged rings are.


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This unique feature will enable physiological neuro-electrical transmission to occur with exceptional high efficiency as only minimal numbers of the conduction electrons will actually pass through a neuro-MT within unit time. Even if we assume that the kinetic energy K of a slow conduction electron is as low as 0.1 eV, its estimated de Brodie wavelength (λ) of the electrons would be 3.88 nm, which is still smaller than the inner radius (~7 nm) of a neuro-MT. This is probably why neuro-MTs have a relatively large inner radius size, as it would enable the conduction of electrons with a very low speed inside neuro-MTs and thereby would help to conserve cellular energy during neuro-electrical transmission.

In addition, the presence of the consecutive dipole ring structures inside a neuro-MT would help terminate the conduction band with high efficiency, i.e., the electric current will end as soon as the neural stimulation (in the form of an action potential) ends (explained in [Figure 3]B). This unique feature is in line with the known characteristics of physiological neuro-electrical activities (for instance, the voluntary muscle contraction can be initiated at will almost instantaneously, and they can also be terminated immediately without any lingering after-effects). Because of this unique feature, the collision-free slow electric conduction occurring inside a neuro-MT is considered to be a unique form of quasi-superconductivity in nature.

Due to the circular forces exerted evenly on the conduction electrons by the consecutive cylindrical dipoles (made of α/β-tubulin heterodimers) [Figure 3]A, it is hypothesized that the conduction electrons will be moving in a ballistic manner at or near the center of the hallow, vacuum neuro-MTs.

Lastly, it is of note that earlier studies have shown that neuro-MTs can serve as a charge storage device (Sataric et al., 1993; Kalra et al., 2020). It is estimated that the capacitance (C) for a single ring of a MT including its carboxy-terminal tails is approximately 1.3 × 10–15 F (Sataric et al., 2009). When the MT is extended to 20 pm in length, the estimated value of C is 3 × 10–12 F. Based on earlier simulation analysis (Tuszyński et al., 2005; Satarić et al., 2009; Sekulić et al., 2011), the capacitance likely arises from a number of sources, including the dense counterion condensation on the MT surface. The large capacitance of neuro-MTs for electrons is an important feature which would enable them to fulfill the proposed physiological function in mediating neuro-electrical transmission on a constant basis. As such, the two unique features of neuro-MTs (i.e., a quasi-superconductor and a charge storage device) may jointly help fulfill their unique physiological functions in neuro-electrical transmission.


  Role of Neuro-Microtubules’ Polarity in Neuro-Electrical Transmission Top


Most neurons in humans have axons and dendrites. Axons vary greatly in length, with some extending more than 1 m within the body. Most axons in the brain are very thin (0.2–20 μm in diameter) compared with their cell bodies (usually ≥ 50 μm). It is known that the neurons have a distinct dynamic polarization, i.e., the electrical signals (action potentials) in a neuron flow in only one direction: from the postsynaptic sites of the neuron, usually the dendrites and cell body, to the beginning part (the trigger zone) of the axon. From there, the action potential is propagated along the entire length of the axon to its terminals. In most neurons studied to date, electrical signals in fact travel only along the axon in one direction (Kandel et al., 2021).

Studies have shown that neuro-MTs have a unique polarity that matches the directions of neuro-electrical transmission. Axonal MTs in a variety of neuronal types have a uniform plus-endout polarity, i.e., the fast-growing plus end of a neuro-MT in the axon is at the distal end of the axon and has the exposed β-tubulin subunits, while the slow-growing minus end which has the exposed α-tubulin subunits is located at or near the neuronal cell body (Baas et al., 1988; Stepanova et al., 2003; Maniar et al., 2011; Kleele et al., 2014; Yau et al., 2014; Rolls and Jegla, 2015; Shorey et al., 2021) (depicted in [Figure 1]B). However, MTs in dendrites have a minus-end-out polarity (Baas et al., 1988; Stone et al., 2008; Baas and Lin, 2011; Rolls and Jegla, 2015; Shorey et al., 2021), i.e., they have an opposite polarity compared to what is seen in axons. In all non-neuronal cells, there is no such polarity for MTs, and they usually grow from the centrosomes located at or near the center of the cell toward the plasma membrane and form a radial system (Muroyama and Lechler, 2017; Sanchez and Feldman, 2017).

Therefore, the unique polarity of neuro-MTs in the axons and dendrites of nerve cells matches the dynamic polarization of electric transmission in nerve cells, which offers support for the hypothesis that neuro-MTs which are densely packed inside axons and dendrites have a suitable structure to mediate neuroelectrical transmission.


  Myelin Sheath May Absorb Electromagnetic Fields Generated by Neuro-Microtubules inside Axons Top


It is known that large axons (and also some large dendrites) are wrapped in multiple layers of myelin sheath [Figure 4]A). The number of layers of myelin sheath around an axon is proportional to the diameter of the axon - larger axons have thicker sheaths. Notably, axons with very small diameters often are not myelinated.{Figure 4}

Two different types of glial cells, i.e., oligodendrocytes in the brain and Schwann cells in the peripheral nervous system, fulfill this function. While one Schwann cell produces a single myelin sheath for one segment of an axon, it is estimated that one oligodendrocyte may produce myelin sheaths for segments of as many as 30 axons.

In the literature, the functions of myelin sheath traditionally include two: one is for insulation of the electrical transmission (in the form of action potentials) along large axons and dendrites, preventing electric currents from leaking out (Kandel et al., 2021), and the other function is for the saltatory nerve conduction (Stadelmann et al., 2019). In view of the proposed role of neuro-MTs in mediating neuro-electrical transmission, it is hypothesized that another important function of the myelin sheath is to serve as a shield that can effectively absorb electromagnetic (EM) fields generated by the quasisuperconducting electrons inside neuro-MTs. To explain the underlying mechanism, it is hypothesized that the multiple layers of myelin sheath can be viewed as a unique consecutive dipole sheet-like structure (depicted in [Figure 4]B−[Figure 4]D). This structure would be perfectly suited to provide an effective shield against the EM fields in such a manner that the axon of one neuron would not interfere with the axons of the neighboring neurons electromagnetically. It is known that the electric currents formed inside axonal neuro-MTs are transient on-andoff currents (usually only lasting for a few milliseconds), and as expected, these currents would always produce a circular EM field around the conducting axon (depicted in [Figure 4]B). Because of the rapid on-and-off nature of the transient axonal currents, the rapidly-changing circular EM field around the axon would induce the formation of electric micro-currents inside the dipole sheets. The induced currents would produce EM fields of their own, which would counteract the original EM field produced by the axon. In fact, the magnitude of the induced EM fields by the surrounding myelin sheaths would depend on the magnitude of the initial EM field produced by the conducting axon. A larger EM field produced by the conducting axon would always induce stronger micro-currents in the myelin sheath along with stronger counteracting EM fields, until the net EM field reaches zero (assuming that there are sufficient layers of myelin sheath to produce the required counteracting magnetic fields).

Here it is of note that the layers of myelin sheath that are closer to the axon would be exposed to a stronger EM field, and thus would induce stronger micro-currents together with the counteracting EM fields. Understandably, the outer layers of myelin sheath would be exposed to significantly lower levels of the EM field, because it has been diminished by the counteracting EM fields produced by the inner layers of myelin sheath. Another factor is the slightly longer distance away from the center of the axon; this likely is a relatively minor factor as the distance is very short. As a result, the induced micro-currents in the outer layers of the myelin sheath are much weaker, and so are counteracting EM fields. Continuing in this line of thoughts, it is further speculated that the most outer layer(s) of the myelin sheath (where the cell body and nucleus are also located nearby) may have the ability to sense the induced micro-currents or the counteracting EM fields in such a way that when the cell can no longer sense the induced micro-currents or the counteracting EM fields, they would stop producing additional layers of myelin sheath. With this proposed mechanism, the Schwann cells in the peripheral nervous system (or oligodendrocytes in the brain) can precisely regulate the number of myelin layers needed to effectively shield the EM fields of axons (and certain dendrites) of varying sizes.

Understandably, therefore, more layers of myelin sheath would be needed to wrap around a larger axon to contain its EM field because the axon has more neuro-MTs and is associated with a stronger electric current and a stronger EM field. Likewise, axons with smaller diameters would need fewer layers of myelin sheath, and those axons with very small diameters often are even not myelinated at all. This fact also suggests that the myelin sheath is not an absolute necessity for the normal process of neuro-electrical transmission.


  Relationship between Neuro-Microtubule-Mediated Neuro-Electrical Transmission and the Saltatory Conduction of Action Potentials Top


In a neuron with a myelinated axon, the action potential is usually initiated at the nonmyelinated initial segment of the axon (i.e., the trigger zone) (Bean, 2007), and then propagates to the synapses (usually located at the far end of the axon), the sites at which signals flow from one neuron to other receiving neurons. The trigger zone of an axon has the highest density of voltage-sensitive Na+ channels and the lowest threshold for generating an action potential (Bean, 2007; Debanne et al., 2011); accordingly, almost all input signals (i.e., the summation of all receptor and synaptic potentials) spreading to the trigger zone of an axon are more likely to produce an action potential than at other sites of the neuron.

It was generally believed that because the capacitance of the myelinated segment of an axon is relatively small, the electric potential formed at the trigger zone is not adequate to discharge the capacitance along the entire length of the myelinated axon (Kandel et al., 2021). To prevent the action potential from dying out, the myelin sheath is interrupted every 1−2 mm by the nodes of Ranvier, which are bare patches of axon membrane approximately 1 μm in length. The nodal membrane is rich in voltage-gated Na+ channels, with density approximately 50 times greater in this region than in myelin-sheathed regions of the axon (Rosenbluth, 1976; Ritchie and Rogart, 1977). This region can more readily generate a strong inward depolarizing Na+ current in response to the passive spread of depolarization down the axon. As such, it is believed that the regularly-distributed nodes of Ranvier would help to periodically boost the amplitude of the action potential, preventing it from decaying with distance.

Also, it is widely held the notion that the action potential can spread rapidly along the internodal regions due to the low capacitance of the myelin sheath, but it slows down as it crosses the high-capacitance region of each bare node. Consequently, as the action potential moves down the axon, it appears to jump quickly from node to node. For this reason, the action potential in a myelinated axon is said to move by saltatory conduction (Huxley and Stampfli, 1949; Hodgkin, 1964; Moore et al., 1978). Because ions flow across the membrane only at the nodes in myelinated fibers, saltatory conduction is also favorable from a metabolic standpoint. Less energy would be expended by the Na+−K+ pump to restore the Na+ and K+ concentration gradients.

In light of the proposed hypothesis that neuro-MTs are involved in neuro-electrical transmission, the traditionally-accepted mechanism for the saltatory conduction of action potentials along a myelinated axon would need some modifications, which are discussed below.

First, let us use the axon of a spinal cord motor neuron as an example to help explain the process. If we assume that an electrical stimulation from the brain reaches the spinal cord motor neuron and adequately activates its axonal trigger zone membrane, then an action potential will be generated, which will then lead to the activation of all neuro-MTs inside the axon, along with the formation of electric currents in all neuro-MTs contained in the axon. Since a motor neuron usually innervates thousands of muscle fibers, a synchronized activation of all muscle fibers innervated by a motor neuron would beneficially produce a synchronized contraction of all muscle fibers. As such, it is also understood that the large axon of a motor neuron would always need to have thicker layers of myelin sheath to contain the stronger EM field as the large numbers of neuro-MTs inside a motor neuron’s axon would always be activated simultaneously, which is expected to generate a stronger EM field.

Second, as mentioned above, for a motor neuron in the spinal cord, an action potential is generated at each node of Ranvier, and as such, the action potential is transmitted along the axon in a saltatory manner. Regarding the mechanism of the saltatory conduction of action potentials along an axon, a new explanation is postulated on the basis of neuro-MT-mediated electrical transmission. As depicted in [Figure 5], the initial action potential induced at or near the trigger zone of a motor neuron would lead to activation of all neuro-MTs contained inside a large axon, which means the formation and flowing of the conduction electrons inside all the MTs in a direction from the farther end of the axon toward the neuronal cell body. The formation of negatively-charged electrons inside the MTs would attract the gathering of positively-charged ions outside neuro-MTs. It is known that the action potentials are more readily induced in the nodes of Ranvier region compared to other membrane regions that are covered with the myelin sheath as the plasma membrane at this region contains high-density Na+ channels and is more sensitive to reductions in the resting membrane potential. As such, when positively-charged ions gather outside neuro-MTs at or near the node of Ranvier, this would result in local reductions in the intracellular resting membrane potential and would then induce the opening of Na+ channels, resulting in the formation of an action potential.
Figure 5: Neuro-microtubule (MT)-mediated neuro-electrical transmission via nodes of Ranvier.
Note: The action potential (AP) is initiated at the nonmyelinated trigger zone, and then leads to the activation of all MTs inside the axon, along with the formation of electric currents inside all MTs. The formation of negatively-charged electrons inside the MTs would attract the gathering of positively-charged ions outside neuro-MTs. APs are more readily induced in the nodes of Ranvier region compared to other membrane regions covered with myelin sheath because the plasma membrane at this special region contains high-density Na+ channels and is more sensitive to reductions in the resting membrane potentials.


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According to the above explanation, it is hypothesized that the action potentials are only selectively elicited at each node of Ranvier of the axon, and they are not formed at the myelinated segments of the axon. It has been known for years that the speed of neuro-electrical transmission between the nodes of Ranvier (i.e., in the myelinated axonal segments) appears to be much faster than at the nodes of Ranvier (Huxley and Stampfli, 1949; Hodgkin, 1964; Moore et al., 1978; Kandel et al., 2021). This phenomenon can be fully understood in the light of the new explanation provided above. It is postulated that action potentials are not formed and also not needed in the myelinated regions of the axon; the neuro-electrical transmission in these regions is solely accomplished through neuro-MT-mediated neuroelectrical transmission. Since the electrical transmission inside a neuro-MT is quasi-superconducting in nature, the transmission would be very fast and essentially without resistivity.

Based on the above explanation, it is understood that in the case of a spinal cord motor neuron, when an action potential is generated at the trigger zone of an axon, all neuro-MTs contained in that axon would be concomitantly activated. Because an action potential usually only lasts approximately 1 millisecond, and also because some motor and sensory nerves are very long (> 1 m in length), continuous firing of an action potential at every node of Ranvier would effectively help maintain the electric potential required for the axonal neuro-MTs to sustain electric transmission until the electric signal reaches the intended target (e.g., the muscle fibers) to elicit a proper action or response. Another potential benefit of having an action potential at every node of Ranvier would help ensure that all MTs contained in the long axon are fully activated, which would be important to fulfilling its intended physiological functions of inducing a synchronized contraction of a large number of muscle fibers.

Third, while it is believed that an action potential is generated at each node of Ranvier for the axons of the spinal cord motor neurons, the situation may only represent a special case and may not be applicable to many other neurons in the brain. In fact, it is questioned here as to whether electrical transmission along the myelinated axons of neurons really requires the activation of every node of Ranvier? Since electrical transmission can readily take place in many neurons in the absence of myelin sheath, this clearly suggests that the presence of nodes of Ranvier is not an absolute necessity for the process of neuro-electrical transmission.

As we know, the axon of a brain neuron may form synapses with as many as 1000 postsynaptic neurons. If all neuro-MTs inside the axon of this neuron are concomitantly activated, then it would mean that all postsynaptic neurons will be activated every time in the same fashion. This hypothetical scenario appears to be very non-physiological. It is speculated that under most conditions, the action potential may not be needed at or near the trigger zone and at every node of Ranvier during neuro-electrical transmission between many types of neurons present in the brain. Further along this line of thoughts, it is speculated that there are actually far fewer nodes of Ranvier in most brain neurons, and the main functions of the myelin sheath formed by oligodendrocytes in the brain are for effective insulation of the electrical currents and also for the effective containment (shielding) of the EM fields produced by the axons of brain neurons.

Lastly, as schematically depicted in [Figure 6], it is hypothesized that neuro-MTs can readily achieve selective transmission of electric signals from a series of closely-connected neurons (usually with very short axons and dendrites) without the need to fire full-scale action potentials. It is speculated that this form of neuro-electrical transmission is widespread among many types of brain neurons. The potential advantages of neuro-MT-mediated neuro-electrical transmission may not be readily achieved by the traditional mode of action potential-based neuro-electrical transmission.
Figure 6: It is hypothesized that neuro-MT-mediated neuro-electrical transmission can achieve selective transmission of signals from a series of closely-connected neurons in the brain.
Note: It is known that the axon of a brain neuron may form synapses with as many as 1000 postsynaptic neurons. For ease of explanation, each neuron (red, blue, purple and yellow neurons) as schematically depicted is assumed to only have 5 dendritic synapses which can receive specific signals from the upstream neurons. Activation of a synapse associated with one of the dendrites (such as dendrite b) of the red neuron can lead to selective activation of the two blue neurons without activating other blue neurons. Similarly, the two blue neurons selectively activated by the red neuron can further activate their own selected downstream neurons (i.e., one purple neuron and one yellow neuron) without activating other neurons. In this way, there are numerous activation patterns of the complex neuronal networks. The selective activation of different neuronal networks is enabled by neuro-MT-mediated selective transmission of the electric signals. In the same way, the dendrites a, c, d, e and f of the red neuron may also activate their selected neurons. Here it should be noted that using the red neuron as an example, all of its 5 dendrites can be simultaneously activated by the upstream neurons, and each dendrite (along with its synapses and receptors) can perform its/their independent functions by sending out specific signals to the selected downstream neurons. Importantly, activation of all red neuron-associated neuronal networks can take place independently at the same time, which means that each neuronal network is not affected by other networks which are transmitted by the same neuron. To put it figuratively, a single neuronal cell is somewhat like a huge office complex with many (such as 1000) land-based telephones in it, and each telephone has its own wiring and thus can function independently without interference from other telephones. These independent and complex functions of neuronal networks are readily enabled by neuro-MT-mediated neuro-electrical transmission (represented by the thin black lines inside the neurons and between the neurons).


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  Concluding Remarks Top


In this paper, a new hypothesis is developed, which suggests that neuro-MTs may function as unique nano-sized bio-devices that can mediate electrical transmission with a unique quasisuperconducting property. It is hypothesized that GTP hydrolysis by each α-/ß-tubulin subunit will help relocate and release free electrons that form conduction electrons inside the vacuum neuro-MTs. It is of note that the strict polarity of neuro-MTs in axons and dendrites matches perfectly the dynamic polarization of nerve cells, which offers support for the hypothesis that neuro-MTs, which are densely packed inside axons and dendrites, have suitable structural organization to mediate neuro-electrical transmission.

Owing to the consecutive dipole ring structures of a neuro-MT, the speed of the conduction electrons in each neuro-MT is expected to be far slower than usual. This unique feature will enable physiological neuro-electrical transmission to take place with high energy efficiency. It is believed that the conduction electrons will be moving in a ballistic manner in the center of the hallow neuro-MT, due to the circular forces exerted evenly on the conduction electrons by the consecutive cylindrical dipoles. Further, the dipole ring structures of a neuro-MT would help terminate the electron conduction with high efficiency.

In addition to serving as an effective insulator for neuroelectrical transmission along large axons and dendrites, it is hypothesized that another important function of the myelin sheath is for the effective containment and shielding of the significant EM fields generated by the conduction electrons inside the quasi-superconducting neuro-MTs. On the basis of the consecutive dipole sheet structures of the myelin sheath, a tentative explanation of the mechanism by which the myelin sheath serves to contain or shield EM fields is also tendered.

Lastly, a new hypothesis is postulated to explain the mechanism of the saltatory conduction of action potentials along an axon, on the basis of neuro-MT-mediated electric transmission. Different from motor neurons, it is speculated that there are far fewer nodes of Ranvier in most brain neurons, and the main functions of the myelin sheath formed by oligodendrocytes around the axons of brain neurons are for the effective insulation of the electrical currents and especially for the effective containment or shielding of the EM fields produced by neuronal axons, but not for saltatory conduction of action potentials. Lastly, it is speculated that neuro-MTs can readily achieve selective transmission of electric signals from a series of closely-connected neurons (with very short axons and dendrites) in the absence of action potentials.

Author contributions

The author contributed solely to the entire content of this theoretical paper.

Conflicts of interest

The author declares that he has no competing interests.

Open access statement

This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.[50]



 
  References Top

1.
Alushin GM, Lander GC, Kellogg EH, Zhang R, Baker D, Nogales E (2014) High-resolution microtubule structures reveal the structural transitions in αβ-tubulin upon GTP hydrolysis. Cell 157:1117-1129.  Back to cited text no. 1
    
2.
Baas PW, Lin S (2011) Hooks and comets: The story of microtubule polarity orientation in the neuron. Dev Neurobiol 71:403-418.  Back to cited text no. 2
    
3.
Baas PW, Deitch JS, Black MM, Banker GA (1988) Polarity orientation of microtubules in hippocampal neurons: uniformity in the axon and nonuniformity in the dendrite. Proc Natl Acad Sci U S A 85:8335-8339.  Back to cited text no. 3
    
4.
Bardeen J, Cooper LN, Schrieffer JR (1957) Microscopic theory of superconductivity. Phys Rev 106:162-164.  Back to cited text no. 4
    
5.
Bean BP (2007) The action potential in mammalian central neurons. Nat Rev Neurosci 8:451-465.  Back to cited text no. 5
    
6.
Craddock TJ, Beauchemin C, Tuszynski JA (2009) Information processing mechanisms in microtubules at physiological temperature: Model predictions for experimental tests. Biosystems 97:28-34.  Back to cited text no. 6
    
7.
Debanne D, Campanac E, Bialowas A, Carlier E, Alcaraz G (2011) Axon physiology. Physiol Rev 91:555-602.  Back to cited text no. 7
    
8.
Garvalov BK, Zuber B, Bouchet-Marquis C, Kudryashev M, Gruska M, Beck M, Leis A, Frischknecht F, Bradke F, Baumeister W, Dubochet J, Cyrklaff M (2006) Luminal particles within cellular microtubules. J Cell Biol 174:759-765.  Back to cited text no. 8
    
9.
Grafstein B, Forman DS (1980) Intracellular transport in neurons. Physiol Rev 60:1167-1283.  Back to cited text no. 9
    
10.
Gudimchuk NB, McIntosh JR (2021) Regulation of microtubule dynamics, mechanics and function through the growing tip. Nat Rev Mol Cell Biol 22:777-795.  Back to cited text no. 10
    
11.
Hodgkin AL (1964) Saltatory conduction in myelinated nerve. In: The conduction of the nervous impulse. The Sherrington Lectures, VII (Hodgkin AL, ed), pp 47-55. Liverpool: Liverpool University Press.  Back to cited text no. 11
    
12.
Hollenbeck PJ, Saxton WM (2005) The axonal transport of mitochondria. J Cell Sci 118:5411-5419.  Back to cited text no. 12
    
13.
Huxley AF, Stampfli R (1949) Evidence for saltatory conduction in peripheral myelinated nerve fibres. J Physiol 108:315-339.  Back to cited text no. 13
    
14.
Kalra AP, Patel SD, Bhuiyan AF, Preto J, Scheuer KG, Mohammed U, Lewis JD, Rezania V, Shankar K, Tuszynski JA (2020) Investigation of the electrical properties of microtubule ensembles under cell-like conditions. Nanomaterials (Basel) 10:265.  Back to cited text no. 14
    
15.
Kandel ER, Koester JD, Mack SH, Siegelbaum SA (2021) Membrane potential and the passive electrical properties of the neuron. In: Principles of neural science, 6th ed. New York, NY: McGraw Hill.  Back to cited text no. 15
    
16.
Kleele T, Marinković P, Williams PR, Stern S, Weigand EE, Engerer P, Naumann R, Hartmann J, Karl RM, Bradke F, Bishop D, Herms J, Konnerth A, Kerschensteiner M, Godinho L, Misgeld T (2014) An assay to image neuronal microtubule dynamics in mice. Nat Commun 5:4827.  Back to cited text no. 16
    
17.
Li H, DeRosier DJ, Nicholson WV, Nogales E, Downing KH (2002) Microtubule structure at 8 A resolution. Structure 10:1317-1328.  Back to cited text no. 17
    
18.
Löwe J, Li H, Downing KH, Nogales E (2001) Refined structure of alpha beta-tubulin at 3.5 A resolution. J Mol Biol 313:1045-1057.  Back to cited text no. 18
    
19.
Luchko T, Huzil JT, Stepanova M, Tuszynski J (2008) Conformational analysis of the carboxy-terminal tails of human beta-tubulin isotypes. Biophys J 94:1971-1982.  Back to cited text no. 19
    
20.
Maniar TA, Kaplan M, Wang GJ, Shen K, Wei L, Shaw JE, Koushika SP, Bargmann CI (2011) UNC-33 (CRMP) and ankyrin organize microtubules and localize kinesin to polarize axon-dendrite sorting. Nat Neurosci 15:48-56.  Back to cited text no. 20
    
21.
Mershin A, Kolomenski AA, Schuessler HA, Nanopoulos DV (2004) Tubulin dipole moment, dielectric constant and quantum behavior: computer simulations, experimental results and suggestions. Biosystems 77:73-85.  Back to cited text no. 21
    
22.
Moore JW, Joyner RW, Brill MH, Waxman SD, Najar-Joa M (1978) Simulations of conduction in uniform myelinated fibers. Relative sensitivity to changes in nodal and internodal parameters. Biophys J 21:147-160.  Back to cited text no. 22
    
23.
Muroyama A, Lechler T (2017) Microtubule organization, dynamics and functions in differentiated cells. Development 144:3012-3021.  Back to cited text no. 23
    
24.
Nogales E (2000) Structural insights into microtubule function. Annu Rev Biochem 69:277-302.  Back to cited text no. 24
    
25.
Nogales E, Wolf SG, Downing KH (1998) Structure of the alpha beta tubulin dimer by electron crystallography. Nature 391:199-203.  Back to cited text no. 25
    
26.
Nogales E, Whittaker M, Milligan RA, Downing KH (1999) Highresolution model of the microtubule. Cell 96:79-88.  Back to cited text no. 26
    
27.
Portet S, Tuszyński JA, Hogue CW, Dixon JM (2005) Elastic vibrations in seamless microtubules. Eur Biophys J 34:912-920.  Back to cited text no. 27
    
28.
Ritchie JM, Rogart RB (1977) Density of sodium channels in mammalian myelinated nerve fibers and nature of the axonal membrane under the myelin sheath. Proc Natl Acad Sci U S A 74:211-215.  Back to cited text no. 28
    
29.
Roll-Mecak A (2015) Intrinsically disordered tubulin tails: complex tuners of microtubule functions? Semin Cell Dev Biol 37:11-19.  Back to cited text no. 29
    
30.
Rolls MM, Jegla TJ (2015) Neuronal polarity: an evolutionary perspective. J Exp Biol 218:572-580.  Back to cited text no. 30
    
31.
Rosenbluth J (1976) Intramembranous particle distribution at the node of Ranvier and adjacent axolemma in myelinated axons of the frog brain. J Neurocytol 5:731-745.  Back to cited text no. 31
    
32.
Sanchez AD, Feldman JL (2017) Microtubule-organizing centers: from the centrosome to non-centrosomal sites. Curr Opin Cell Biol 44:93-101.  Back to cited text no. 32
    
33.
Sataric MV, Tuszynski JA, Zakula RB (1993) Kinklike excitations as an energy-transfer mechanism in microtubules. Phys Rev E Stat Phys Plasmas Fluids Relat Interdiscip Topics 48:589-597.  Back to cited text no. 33
    
34.
Satarić MV, Ilić DI, Ralević N, Tuszynski JA (2009) A nonlinear model of ionic wave propagation along microtubules. Eur Biophys J 38:637647.  Back to cited text no. 34
    
35.
Scott A (1992) Davydov's soliton. Phys Rep 217:1-67.  Back to cited text no. 35
    
36.
Sekulić DL, Satarić BM, Tuszynski JA, Sataric MV (2011) Nonlinear ionic pulses along microtubules. Eur Phys J E Soft Matter 34:49.  Back to cited text no. 36
    
37.
Shorey M, Rao K, Stone MC, Mattie FJ, Sagasti A, Rolls MM (2021) Microtubule organization of vertebrate sensory neurons in vivo. Dev Biol 478:1-12.  Back to cited text no. 37
    
38.
Soppina V, Herbstman JF, Skiniotis G, Verhey KJ (2012) Luminal localization of α-tubulin K40 acetylation by cryo-EM analysis of fablabeled microtubules. PLoS One 7:e48204.  Back to cited text no. 38
    
39.
Stadelmann C, Timmler S, Barrantes-Freer A, Simons M (2019) Myelin in the central nervous system: structure, function, and pathology. Physiol Rev 99:1381-1431.  Back to cited text no. 39
    
40.
Stepanova T, Slemmer J, Hoogenraad CC, Lansbergen G, Dortland B, De Zeeuw CI, Grosveld F, van Cappellen G, Akhmanova A, Galjart N (2003) Visualization of microtubule growth in cultured neurons via the use of EB3-GFP (end-binding protein 3-green fluorescent protein). J Neurosci 23:2655-2664.  Back to cited text no. 40
    
41.
Stone MC, Roegiers F, Rolls MM (2008) Microtubules have opposite orientation in axons and dendrites of Drosophila neurons. Mol Biol Cell 19:4122-4129.  Back to cited text no. 41
    
42.
Stracke R, Böhm KJ, Wollweber L, Tuszynski JA, Unger E (2002) Analysis of the migration behaviour of single microtubules in electric fields. Biochem Biophys Res Commun 293:602-609.  Back to cited text no. 42
    
43.
Sui H, Downing KH (2010) Structural basis of interprotofilament interaction and lateral deformation of microtubules. Structure 18:10221031.  Back to cited text no. 43
    
44.
Tilney LG, Bryan J, Bush DJ, Fujiwara K, Mooseker MS, Murphy DB, Snyder DH (1973) Microtubules: evidence for 13 protofilaments. J Cell Biol 59:267-275.  Back to cited text no. 44
    
45.
Tuszyński JA, Brown JA, Crawford E, Carpenter EJ, Nip MLA, Dixon JM, Satarić MV (2005) Molecular dynamics simulations of tubulin structure and calculations of electrostatic properties of microtubules. Math Comput Modell 41:1055-1070.  Back to cited text no. 45
    
46.
Unger E, Böhm KJ, Vater W (1990) Structural diversity and dynamics of microtubules and polymorphic tubulin assemblies. Electron Microsc Rev 3:355-395.  Back to cited text no. 46
    
47.
Vallee RB, Bloom GS (1991) Mechanisms of fast and slow axonal transport. Annu Rev Neurosci 14:59-92.  Back to cited text no. 47
    
48.
van den Heuvel MG, de Graaff MP, Lemay SG, Dekker C (2007) Electrophoresis of individual microtubules in microchannels. Proc Natl Acad Sci U S A 104:7770-7775.  Back to cited text no. 48
    
49.
Yau KW, van Beuningen SF, Cunha-Ferreira I, Cloin BM, van Battum EY, Will L, Schätzle P, Tas RP, van Krugten J, Katrukha EA, Jiang K, Wulf PS, Mikhaylova M, Harterink M, Pasterkamp RJ, Akhmanova A, Kapitein LC, Hoogenraad CC (2014) Microtubule minus-end binding protein CAMSAP2 controls axon specification and dendrite development. Neuron 82:1058-1073.  Back to cited text no. 49
    
50.
Zhu BT (2022) An important structural requirement for the superconductor material. arXiv:2207.01226.  Back to cited text no. 50
    


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  [Figure 1], [Figure 2], [Figure 3], [Figure 5], [Figure 6]



 

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