How are the subunits in the acetylcholine receptor (AChR) organized in myasthenia gravis (MG)?

Updated: Aug 27, 2018
  • Author: Abbas Jowkar, MD; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Answer

The subunits in the AChRs are organized like barrel staves with their convexity inward or in a funnel-like fashion with the narrow end oriented to the intracellular compartment. In the center of the funnel-like portion of the AChR is a cation channel, which is contributed by the M2 and M3 domains of each subunit. Negatively charged residues located at either end of the channel allow the passage of positive ions and exclude passage of the negative ions. Ion binding sites within the channel have an important role in the passage of ions. The ACh binding sites and the main immunogenic region (MIR) are located on the protruding extracellular surfaces of alpha subunits; although in close proximity, the sites for MIR and ACh are distinctly separate. The AChR binding sites are actually located between the α1 and δ subunits and between the α2 and ε subunits. The extracellular portions of AChR extend 100 Angstrom units beyond the cell membrane. Sugars on the extracellular surface of the subunits extend outward and have complex branching patterns. On the cytoplasmic surface of the membrane are cytoskeletal components, which anchor the AChRs. The post-synaptic junctional folds are packed with AChRs (10,000 receptors/µm2) and also contain other protein subsets like MuSK, LRP4, rapsyn, integrins, ErbB receptors, N-acetylgalactosaminlyl transferase, and collagen XIII. [18, 19] Complex interactions between agrin, rapsyn, and MuSK, and LRP4 are involved in the development and maintenance of the NMJ. The clustering of AChR at the crests of the postsynaptic junctional fold is critical for normal neuromuscular transmission.

The troughs of the junctional folds have neural cell adhesion molecules (NCAM), and the voltage-gated sodium ion channels. The latter are tethered to Ankyrin G and β-spectrin, and linked to the cytoskeleton by syntrophins. [20, 21]  At the endplate, rapsyn connects AChRs to each other and muscle fiber cytoskeleton via dystrophin-glycoprotein complex (DGC). The DGC contains a number of transmembrane proteins (α- and β-dystroglycan and the sarcoglycan complex). DGC also has submembrane proteins (dystrophin, utrophin, syntrophin, and dystrobrevin) and connects to the cytoskelton via F-actin and to the basal lamina via laminin.


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