The role of Rapsyn in neuromuscular junction and congenital myasthenic syndrome

Abstract

Rapsyn, an intracellular scaffolding protein associated with the postsynaptic membranes in the neuromuscular junction (NMJ), is critical for nicotinic acetylcholine receptor clustering and maintenance. Therefore, Rapsyn is essential to the NMJ formation and maintenance, and Rapsyn mutant is one of the reasons causing the pathogenies of congenital myasthenic syndrome (CMS). In addition, there is little research on Rapsyn in the central nervous system (CNS). In this review, the role of Rapsyn in the NMJ formation and the mutation of Rapsyn leading to CMS will be reviewed separately and sequentially. Finally, the potential function of Rapsyn is prospected.

Figure 1.

Protein structural diagram and the interacting factors of Rapsyn. (A) Rapsyn’s full length is 412 amino acids, and the mature protein’s first methionine is cut off. Rapsyn links to the postsynaptic membrane via an N-terminal myristoylated site (Gly2). Rapsyn contains a myristylation motif, seven tandem tetratricopeptide repeats (TPRs), a coiled-coil (CC) domain, a Ring-H2 domain, and a phosphorylation motif; (B) The factors interacting with Rapsyn in the NMJ. Most factors are associated with cellular skeletal protein, such as actin filament (F-actin), intermediated filament, and microtube; some form complex with Rapsyn. Rapsyn maintains the nAChR clusters via anchoring with sarcolemma or cellular skeletal protein directly/indirectly. CK2: Casein kinase 2; HSP90β: Heat shock protein 90β; Lrp4: Low-density lipoprotein receptor-related protein 4; MACF1: Microtubule actin cross-linking factor 1; MuSK: Muscle-specific kinase; nAChR: Nicotinic acetylcholine receptor; TPR: Tandem tetratricopeptide repeats; TrkA: Neurotrophic receptor tyrosine kinase 1; NMJ: Neuromuscular junction.

Figure 2.

Rapsyn-dependent signaling pathways in the NMJ end plate. Rapsyn modifies nAChR in several ways, and its stability is also regulated by other factors. (1) Rapsyn can activate tyrosine kinases to phosphorylate nAChR; (2) Rapsyn induces the phosphorylation of nAChR β subunit Y390, and MuSK can enhance the phosphorylation; (3) Rapsyn may be phosphorylated by PKC and then induces nAChR insertion into the membrane; (4) E3 ligase activity of Rapsyn Ring-H2 domain modulates nAChR stability, including neddylation (NEDD), ubiquitination (Ub), and sumoylation (SUMO); (5) Calpain participates in acetylcholine-induced nAChR cluster dispersion, and Rapsyn inhibits its function; (6) HSP90β is necessary for Rapsyn stabilization (arrow means promoting, and vertical crossing lines in red color means inhibiting; “↑” indicates increase, and “↓” shows decrease). Frk: Fyn-related Src family tyrosine kinase; Fyn: FYN proto-oncogene, Src family tyrosine kinase; HSP90β: Heat shock protein 90β; MuSK: Muscle-specific kinase; NEDD: Neddylation; nAChR: Nicotinic acetylcholine receptor; P: Phosphorylation; PKC: Protein kinase C; Src: SRC proto-oncogene, non-receptor tyrosine kinase; SUMO: Sumoylation; Ub: Ubiquitination.

Figure 3.

Mutations of Rapsyn in congenital myasthenic syndrome. Missense mutation or nonsense mutation of Rapsyn is shown in the right panel, and the “X” in the mutation represents nonsense mutation. Insertion and deletion in exon or intron causing frameshift of Rapsyn are shown in the left panel. The number in the left panel represents the nucleus acid number in the cDNA, and the number in the right panel means the amino acid number at the protein level.

Figure 4.

Schematic diagram of the potential role of Rapsyn in the central nervous system. The first important question in the research of Rapsyn’s role in the CNS is what is the cell type expressing Rapsyn. It is unknown whether the Rapsyn function in the CNS is similar to the role in the neuromuscular junction, such as mediating protein clustering, lysosome clustering, and E3 ligase activity. CNS: Central nervous system.