Geon 9. The Role of Ankyrin-G in Excitability Alzheimer

Ankyrin-G plays a crucial role in anchoring various proteins to the plasma membrane, in particular the persistent (non-inactivating) sodium channel, Nav1.6, which has a significant impact on neuronal excitability (O'Brien and Meisler, 2013). Both Ankyrin-G and Nav1.6 are localized predominantly to the axon initial segment (AIS) and nodes of Ranvier. In experiments using TsA201 cells, it was found that Ankyrin-G could modulate the gating property of Nav1.6 (Shirahata et al., 2006). The TsA201 cell expressing Nav1.6 alone exhibited significant persistent sodium current INaP, but co-expression with Ankyrin-G reduced INaP. This observation can readily be explained by employing two microtubule properties:

  1. Microtubules can be anchored to the AIS membrane via interaction with Ankyrin-G (discussed below).
  2. Each tubulin in a microtubule is highly negatively charged (see Baker et al., 2001 and Introduction to Microtubules).

Hence, the association of microtubules with the membrane may exert a hyperpolarizing field on voltage-gated ion channels such as Nav1.6, thereby reducing INaP. Experiments have shown that the anchoring of microtubules to AIS membrane requires not only Ankyrin-G, but also the end-binding proteins, EB1 or EB3 (denoted by EB1/3) (Leterrier et al., 2011). In most cases, EB1/3 binds at the microtubule plus end, regulating its growth and shrinkage. At the AIS, EB1/3 binds along the entire microtubule, and stabilize it at a fixed length. This is because EB1/3 also has weak binding sites along the microtubule. At low concentration, EB1/3 binds preferentially at the plus end which has stronger binding affinity. The weaker binding sites may be occupied only when the EB1/3 concentration is high (Bu and Su, 2001).

Figure 9-1 illustrates the Microtubule Model for Excitability which was originally proposed for wireless communication in the brain where the microtubules in AIS may serve as receiving antennas. These microtubules will be referred to as microtubule antennas. While the AIS of all neurons contains microtubules, only those participating in wireless communication (e.g., long range synchronization) may have microtubule antennas. The Tau protein is likely to modulate neuronal excitability by interfering with the binding between Ankyrin-G and the microtubule (Chapter 10). This model predicts that Tau pathology originates from the neurons containing microtubule antennas.

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Figure 9-1. The Microtubule Model for Excitability.
(A) The association of the negatively charged microtubule with the membrane is mediated by Ankyrin-G and EB1/3. This should reduce excitability.
(B) The oscillating electric field in the electromagnetic wave may cause microtubules to vibrate in the transverse direction.
(C) The vibration of microtubules may result in dissociation from the membrane, thereby increasing excitability. EB1/3 may attach to either Ankyrin-G or microtubule.
(D) The Tau protein may enhance excitability by preventing the association between the microtubule and the membrane.

According to the Microtubule Model for Excitability, decreased Ankyrin-G level should enhance excitability (Figure 9-2).

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Figure 9-2. The effects of Ankyrin-G on excitability.
(A) The association of the negatively charged microtubule with the membrane reduces excitability.
(B) The loss of an anchor point causes a segment of the microtubule to bend away from the membrane, thereby increasing excitability.
(C) The loss of all anchor points causes the entire microtubule to detach from the membrane.

 

Author: Frank Lee
First published: May 23, 2015
Last updated: April 7, 2017