|12. Microtubules As the Receiving Antennas||MT|
The receiving antenna is an essential element in wireless communication which could also be employed by the brain (see previous chapter). Its purpose is to convert the received electromagnetic (EM) waves into other physical forms that can directly affect the receiving system. For instance, the EM waves cannot interact directly with the electric circuit in a radio or television. They must be converted into electric currents by the metal antenna. In the brain, neuronal excitability is fundamentally governed by the opening and closing of ion channels, which in turn depends on membrane potential (membrane voltage). The electric field of EM waves is too weak to open the voltage-gated ion channels directly. Chapter 10 proposes that the microtubules at the the axon initial segment (AIS) could amplify the EM signals. Further details are discussed below.
How the Microtubule Antenna Works
The association of a negatively charged microtubule with the membrane from the intracellular side is equivalent to application of a hyperpolarizing field on the membrane. Dissociation of the microtubule from the membrane has the same effect as depolarization. Hence, microtubules can be used to regulate neuronal excitability, especially if they are localized to the axon initial segment (AIS), which contains high density of voltage gated ion channels. Nerve impulses (action potentials) are initiated at the AIS (Buffington and Rasband, 2011).
Ankyrin-G, end-binding proteins and the Tau protein have been demonstrated to regulate the association between microtubules and the membrane. In the absence of external forces, a microtubule fascicle may be anchored to the membrane by Ankyrin-G and the microtubule end-binding protein, EB1 or EB3 (denoted by EB1/3). The membrane-bound microtubule fascicle has inhibitory effects on neuronal firing. Similar to the interaction with metal antenna, the EM wave may exert a force on the negatively charged microtubules. Its alternating electric field may cause the membrane-bound microtubules to vibrate in the transverse direction, resulting in dissociation from the membrane (Figure 1). This should increase excitability.
The Role of Ankyrin-G
Ankyrin-G, encoded by the ANK3 gene, plays a pivotal role in anchoring various proteins to the membrane, including microtubules (Figure 1). The "giant anchor" is located predominately at AIS and nodes of Ranvier (Iqbal et al., 2013). In experiments using TsA201 cells, it was found that Ankyrin-G could suppress the sodium current through Nav1.6 (Shirahata et al., 2006), which is a type of sodium channels that do not inactivate (O'Brien and Meisler, 2013). This observation supports the view that anchoring of microtubules to the membrane by Ankyrin-G has the same effects as hyperpolarization.
The persistent (non-inactivating) sodium channel, Nav1.6, is enriched in AIS, with a crucial role for resonance amplification, namely, enhancing membrane potential oscillation without shifting resonance frequency (Hutcheon and Yarom, 2000; PDF). Many cortical neurons exhibit spontaneous membrane potential oscillation below threshold at the resonance frequency that depends on the intrinsic membrane properties. Then a slight enhancement by the opening of persistent sodium channels can elicit a train of action potentials (spikes) with the original resonance frequency. This feature is important for long range synchronization. Whenever spikes are generated synchronously in one brain region, the emitted EM waves will immediately be received by any neurons in the brain, but only those with the same resonance frequency (e.g., alpha band, theta band, etc.) can join the synchronization.
Over the past few years, experimental studies have provided great insights into the interaction between microtubules and Ankyrin-G, which allows for a more detailed description of the underlying mechanism (Figure 1). It turns out that the microtubule end-binding protein and the microtubule-associated protein Tau are also involved. The Tau protein is a central player in Alzheimer's disease and other neurodegenerative disorders. Its involvement in excitability opens the door for the fundamental understanding of neurodegeneration (discussed in the book, Alzheimer's Disease).
The Role of End-Binding Proteins
The microtubule end-binding protein EB1/3 is required for the binding between the microtubule and Ankyrin-G (Leterrier et al., 2011; Fréal et al., 2016). Normally, EB1/3 binds to the microtubule's plus end, regulating its dynamic growth. However, at the AIS, the microtubule fascicles are decorated by EB1/3 along the entire molecule. This is because the microtubule also possesses other binding sites for EB1/3, albeit weaker. At low concentration, EB1/3 binds preferentially at the plus end which has stronger binding affinity. The weaker binding sites may be occupied when the EB1/3 concentration is high (Bu and Su, 2001).
Ankyrin-G can also bind with EB1/3 through its tail domain (Fréal et al., 2016), which can extend into the intracellular AIS shaft at a maximum depth of ~140 nm, with an average of only 26 nm below the submembrane coat (Jones and Svitkina, 2016). The diameter of the AIS is about 1500 nm. Therefore, most region within the AIS shaft is beyond the reach of Ankyrin-G. The fascicle has ample room to move randomly and exert little influence on channel gating. As the fascicle moves toward the membrane and within the reach of Ankyrin-G, it will be anchored to the membrane, thereby reducing excitability. On the other hand, the EM force may disrupt the interaction among Ankyrin-G, EB1/3, and the microtubule fascicle, causing the fascicle to dissociate from the membrane, thus increasing excitability (Figure 1).
The Role of Tau Proteins
The Tau protein can directly interact with and recruit EB1/3 to the microtubule bundle (Sayas et al., 2015). Thus Tau may interfere with the interaction among Ankyrin-G, EB1/3, and the microtubule fascicle, preventing the fascicle association with the membrane, and consequently enhancing excitability. In animal models, Tau reduction or knockout has been demonstrated to attenuate hyperexcitability (Holth et al., 2013; DeVos et al., 2013; Li et al., 2014).
Author: Frank Lee