Agrin induces phosphorylation of the nicotinic acetylcholine receptor

Wallace, Bruce G.; Qu, Zhican; Richard, Huganir

doi:10.1016/0896-6273(91)90227-q

Cited by 245 publications

(186 citation statements)

References 42 publications

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“…Phosphorylation correlates closely with reduced mobility and detergent extractability of the AChR (Meier et al., 1995, Borges andFerns, 2001), suggesting that it regulates linkage to the cytoskeleton. In addition, it precedes AChR clustering (Ferns et al, 1996) and tyrosine kinase inhibitors that block phosphorylation also block clustering (Wallace et al, 1991, Ferns et al, 1996. Consistent with these findings, mutation of the tyrosine phosphorylation site in the β subunit abolishes agrin-induced cytoskeletal anchoring of mutant AChR and impairs its aggregation in muscle cells (Borges and Ferns, 2001).…”

Section: Nih Public Accesssupporting

confidence: 68%

“…In muscle cells, agrin-or nerve-induced clustering of the receptor involves tyrosine phosphorylation of both the AChR β and δ subunits (Wallace et al, 1991, Meier et al, 1995, Ferns et al, 1996. Following MuSK activation, phosphorylation of each subunit occurs with a similar time-course and is inhibited by the same pharmacological agents , Mohamed et al, 2001.…”

Section: Phosphorylation Of Achr β and δ Subunitsmentioning

confidence: 99%

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Rapsyn carboxyl terminal domains mediate muscle specific kinase–induced phosphorylation of the muscle acetylcholine receptor

et al. 2008

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At the developing vertebrate neuromuscular junction, postsynaptic localization of the acetylcholine receptor (AChR) is regulated by agrin signaling via the muscle specific kinase (MuSK) and requires an intracellular scaffolding protein called rapsyn. In addition to its structural role, rapsyn is also necessary for agrin-induced tyrosine phosphorylation of the AChR, which regulates some aspects of receptor localization. Here, we have investigated the molecular mechanism by which rapsyn mediates AChR phosphorylation. In a heterologous COS cell system, we show that MuSK and rapsyn induced phosphorylation of β subunit tyrosine 390 (Y390) and δ subunit Y393, as in muscle cells. Mutation of β Y390 or δ Y393 did not inhibit MuSK/rapsyn-induced phosphorylation of the other subunit in COS cells, and mutation of β Y390 did not inhibit agrin-induced phosphorylation of the δ subunit in Sol8 muscle cells; thus, their phosphorylation occurs independently, downstream of MuSK activation. In COS cells, we further show that MuSK-induced phosphorylation of the β subunit was mediated by rapsyn, as MuSK plus rapsyn increased β Y390 phosphorylation more than rapsyn alone and MuSK alone had no effect. Intriguingly, MuSK also induced tyrosine phosphorylation of rapsyn itself. We then used deletion mutants to map the rapsyn domains responsible for activation of cytoplasmic tyrosine kinases that phosphorylate the AChR subunits. We found that rapsyn C-terminal domains (amino acids 212-412) are both necessary and sufficient for activation of tyrosine kinases and induction of cellular tyrosine phosphorylation. Moreover, deletion of the rapsyn RING domain (365-412) abolished MuSK-induced tyrosine phosphorylation of the AChR β subunit. Together, these findings suggest that rapsyn facilitates AChR phosphorylation by activating or localizing tyrosine kinases via its C-terminal domains. Keywords neuromuscular junction; synaptogenesis; agrin; postsynaptic membraneAt the developing neuromuscular junction in vertebrates, several nerve-derived signals combine to localize the acetylcholine receptor at postsynaptic sites (Sanes and Lichtman, 2001, Burden, 2002, Kummer et al., 2006. One essential factor is agrin, which signals via the MuSK receptor tyrosine kinase and induces and/or stabilizes clustering of the AChR in the postsynaptic membrane (reviewed in (Kummer et al., 2006 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. is prepatterned and AChR clusters occur in the central region of the muscle prior to and even in the absence of neural innervation (Lin et al., 2001, Yang et al., 2001). However, upo...

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Section: Nih Public Accesssupporting

confidence: 68%

Section: Phosphorylation Of Achr β and δ Subunitsmentioning

confidence: 99%

Rapsyn carboxyl terminal domains mediate muscle specific kinase–induced phosphorylation of the muscle acetylcholine receptor

et al. 2008

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“…Similarly, phosphorylation of the AChR ␤-subunit seems to be required for agrin-induced AChR aggregation (Wallace et al, 1991;Meier et al, 1995Meier et al, , 1996.…”

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confidence: 99%

Neural Agrin Induces Ectopic Postsynaptic Specializations in Innervated Muscle Fibers

Meier¹,

et al. 1997

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Neural agrin, in the absence of a nerve terminal, can induce the activity-resistant expression of acetylcholine receptor (AChR) subunit genes and the clustering of synapse-specific adult-type AChR channels in nonsynaptic regions of adult skeletal muscle fibers. Here we show that, when expression plasmids for neural agrin are injected into the extrasynaptic region of innervated muscle fibers, the following components of the postsynaptic apparatus are aggregated and colocalized with ectopic agrininduced AChR clusters: laminin-␤2, MuSK, phosphotyrosinecontaining proteins, ␤-dystroglycan, utrophin, and rapsyn. These components have been implicated to play a role in the differentiation of neuromuscular junctions. Furthermore, ErbB2 and ErbB3, which are thought to be involved in the regulation of neurally induced AChR subunit gene expression, were colocalized with agrin-induced AChR aggregates at ectopic nerve-free sites. The postsynaptic muscle membrane also contained a high concentration of voltage-gated Na ϩ channels as well as deep, basal lamina-containing invaginations comparable to the secondary synaptic folds of normal endplates. The ability to induce AChR aggregation in vivo was not observed in experiments with a muscle-specific agrin isoform. Thus, a motor neuron-specific agrin isoform is sufficient to induce a full ectopic postsynaptic apparatus in muscle fibers kept electrically active at their original endplate sites.

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“…26 The combination of agrin on its receptor induces an intracellular signalling cascade that includes tyrosine phosphorylation of the AChR itself and of the muscle-specific receptor tyrosine kinase, MuSK. 27,28 Both are phosphorylated rapidly after addition of agrin. The interaction of agrin with MuSK results in the activation of the nonreceptor tyrosine kinases Abl-1 and Abl-2, which directly influence the actin cytoskeleton, 29 confirming similarities between AChR aggregation and focal adhesion formation.…”

mentioning

confidence: 99%

Reduced expression of nicotinic AChRs in myotubes from spinal muscular atrophy I patients

Arnold¹,

Gueye²,

Guettier‐Sigrist³

et al. 2004

Laboratory Investigation

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Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by degeneration of motoneurons and skeletal muscle atrophy. In its most severe form, it leads to death before the age of 2 years. While primary degeneration of motor neurons is well established in this disease, and this results in neurogenic atrophy of skeletal muscle, we have previously reported evidence for a primary muscle defect. In this study, we used primary cultures of embryonic human skeletal muscle cells from patients with SMA and from controls to examine the effects of muscle fiber differentiation in the absence of a nerve component. Cultured SMA skeletal muscle cells are unable to fuse correctly to form multinuclear myotubes, the precursors of the myofibers. We also show that agrin-induced aggregates of nicotinic acetylcholine receptors, one of the earliest steps of neuromuscular junction formation, cannot be visualized by confocal microscopy on cells from SMA patients. In binding experiments, we demonstrate that this lack of clustering is due to defective expression of the nicotinic acetylcholine receptors in the myotubes of SMA patients whereas the affinity of a-bungarotoxin for its receptor remains unchanged regardless of muscle cell type (SMA or control). These observations suggest that muscle cells from SMA patients have intrinsic abnormalities that may affect proper formation of the neuromuscular junction. Keywords: spinal muscular atrophy; myotubes; neuromuscular junction; nicotinic acetylcholine receptors; aggregation; binding Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by degeneration of spinal motor neurons leading to a muscle weakness and paralysis. SMA is traditionally classified into three types based on the age of onset and the severity of symptoms. 1 The SMA I or Werdnig-Hoffmann disease is the most severe form. Patients never attain the ability to sit, and their lifespan does not exceed infancy in most cases. SMA II is the intermediate form. Patients are unable to stand or walk unaided, and death usually occurs in adulthood. SMA III or Kugelberg-Welander disease presents a milder phenotype. Patients are able to stand and walk and present a near-normal life expectancy. The gene responsible for all three types of SMA was mapped to the region 5q11.2-13.3 by linkage analysis. [2][3][4][5] This gene, named SMN for 'survival of motor neurons', is mutated in 98% of the SMA patients, and the majority of mutations occur in exon 7. 6 It encodes a ubiquitously expressed SMN protein present in both the cytoplasm and the nucleus. In this last compartment, the SMN protein is concentrated in structures called gems (for 'gemini of coiled bodies') located in the close proximity of Cajal bodies (previously named coiled bodies). 7,8 The SMN protein participates in the formation of the SMN complex, which is associated with small nuclear ribonucleoproteins (snRNP) in the cytoplasm and plays a crucial role in the spliceosomal snRNP assembly. 9 In the nucleus, the SMN complex participates in the regener...

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Agrin induces phosphorylation of the nicotinic acetylcholine receptor

Cited by 245 publications

References 42 publications

Rapsyn carboxyl terminal domains mediate muscle specific kinase–induced phosphorylation of the muscle acetylcholine receptor

Rapsyn carboxyl terminal domains mediate muscle specific kinase–induced phosphorylation of the muscle acetylcholine receptor

Neural Agrin Induces Ectopic Postsynaptic Specializations in Innervated Muscle Fibers

Reduced expression of nicotinic AChRs in myotubes from spinal muscular atrophy I patients

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