Figure 1.

Schematic representation of the neuromuscular junction (NMJ) and the clustering pathway of acetylcholine receptors (AChRs). (A) On the muscle post-synaptic membrane, low density lipoprotein receptor-related protein 4 (LRP4) and Muscle Specific Kinase (MuSK) form a loose tetramer, and, at this stage, AChRs are dispersed along the sarcolemma. (B) Agrin is secreted by the motor nerve terminal into the synaptic cleft and interacts with LRP4 inducing a conformational change in the LRP4-MuSK tetramer. This leads to MuSK activation through an auto-phosphorylation loop of the tyrosine residues in its intracytoplasmatic domain. (C) The recruitment of DOK7 amplifies MuSK phosphorylation and triggers the phosphorylation cascade downstream that involves several intermediate proteins including Crk, Ckr-l, Abl, and Scr. Concomitantly, a subsidiary pathway leads to cytoskeletal rearrangements through the activation of Rac1 and Rho GTPases. The clustering pathway culminates in the phosphorylation of the subunits of the AChR and the recruitment of rapsyn, which anchors the AChR clusters to the underlying actin filaments. Furthermore, LRP4 participates in presynaptic development through a retrograde signal which increases the clustering of ACh vesicles in the motor nerve terminal. (D) Via the extracellular matrix (ECM), MuSK interacts also with ColQ which, in turn, is attached in tetramers to the enzyme acetylcholinesterase (AChE) responsible for the hydrolysis of acetylcholine (ACh) after its binding to the AChR.