Mutations of the skeletal muscle acetylcholine receptor

Neurology 2012;79:404–405 The skeletal muscle acetylcholine receptor (AChR) is a beautifully functional molecular complex made up of 5 subunits. Acetylcholine binding initiates pore opening, producing the endplate current (EPC); the resulting action potentials travel over the muscle surface and into the transverse tubules, initiating contraction via calcium (Ca ) release from the sarcoplasmic reticulum that interfaces with the transverse tubule network. EPC amplitude and duration is critical for proper functioning of skeletal muscle: if too small or short, it will not effectively activate sodium channels to trigger action potentials; if too long, it will trigger multiple APs. The EPC also conducts Ca into cells, so overly long EPCs will lead to endplate damage due to Ca activation of internal protease systems.1 Congenital disorders of neuromuscular transmission (CDNT), also called congenital myasthenias, allow us to explore the consequences of natural molecular experiments resulting in alteration of structure on the functioning of the AChR. The article by Shen et al.2 illustrates the importance of precise timing of the EPC and provides insights into the molecular operation of the AChR. CDNTs result from a heterogeneous group of mutations involving neuromuscular junction (NMJ) proteins.1 These syndromes usually present within the first year of life with fluctuating weakness involving limb, trunk, and axial muscles. The clinical severity of genetic disorders of the AChR reflects the extent to which the mutations are associated with failure of NMJ transmission.1,3 CDNTs involving the AChR can be associated with altered AChR kinetics, leading to either shorter or longer AChR channel openings. The longer AChR channel openings produce long duration EPCs that produce the physiologic changes that underlie the slow channel syndrome. In contrast, short duration AChR channel openings result in short duration EPCs leading to the impairments in neuromuscular transmission seen in the fast channel syndromes. In addition, mutations involving AChR subunits or molecules associated with AChR insertion or stabilization in the endplate membrane can reduce the number of endplate AChRs, reducing the total current in the EPC. Mutations involving the AChR can reduce its single channel conductance, leading to smaller EPCs or altered kinetics. The fast channel syndrome phenotypes vary depending, in part, upon whether AChR expression or single channel conductance are altered by subunit mutations.1,3 An important observation is that no AChR subunit mutations have resulted in an enhanced safety factor for neuromuscular transmission.4 The NMJ evolved over millions of years, hence it is unlikely that any mutation of NMJ components would lead to improved function. The AChR is composed of 5 subunits, 2 subunits, and 1 copy each of the , , and either the or subunit (see figure 1 of Shen et al.2). The adult form of the AChR found at the neuromuscular junction contains the subunit and the fetal or extrajunctional form of the AChR contains the subunit. The subunit contains the primary binding sites for ACh. CDNTs due to mutations of AChR subunits most commonly involve the subunit. Mutations of the subunit can result in fast channel or slow channel syndrome or disorders with reduced expression of AChRs. ACh binds in the interfaces between the and / subunits and the and subunits. The binding of 2 ACh molecules facilitates sliding or twisting of the AChR subunits, which alters the configuration of the channel pore and enables ionic current to flow.5 Studies of clinical and synthetic AChR subunit mutations have contributed greatly to the present impression, albeit incomplete, of how ACh binding facilitates subunit interactions that lead to AChR channel opening and the subunit interactions leading to channel closure.6–10 For example, the open configuration likely occurs when the AChR subunits are aligned. After both ACh molecules unbind, the AChR subunits would assume a new configuration in which the central pore is narrower. The narrowing might occur by the AChR subunits twisting together,