Tyrosine phosphatase regulation of MuSK-dependent acetylcholine receptor clustering

Madhavan, Raghavan; Zhao, Xiaozheng; Rüegg, Markus A.; Peng, H. Benjamin

doi:10.1016/j.mcn.2004.10.005

Cited by 39 publications

(65 citation statements)

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“…8A). Treatment with another common tyrosine phosphatase inhibitor, pervanadate (Madhavan et al, 2005;Moult et al, 2006), caused the same peri-synaptic staining of recycled AChRs (Fig. 8E,F), without affecting the synaptic localization of pre-existing AChRs (Fig.…”

Section: Proper Localization Of Recycled Receptors Requires Tyrosine mentioning

confidence: 72%

“…To inhibit tyrosine phosphatase activity, we used two agents: phenylarsine oxide (2 mM; Sigma, St Louis, MO) and pervanadate (5-10 mM). Pervanadate solution was prepared by mixing 1.7% H 2 O 2 and sodium orthovanadate (Sigma) in a ratio of 1:50 for 10 minutes before adding it to the sternomastoid muscle (Madhavan et al, 2005). Okadaic acid (10-100 M; Sigma) was used to inhibit serine/threonine phosphatases.…”

Section: Pharmacologymentioning

confidence: 99%

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The dynamics of recycled acetylcholine receptors at the neuromuscular junction in vivo

Bruneau

Akaaboune

2006

Development

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At the peripheral neuromuscular junction (NMJ), a significant number of nicotinic acetylcholine receptors (AChRs) recycle back into the postsynaptic membrane after internalization to intermingle with not-yet-internalized 'pre-existing' AChRs. However, the way in which these receptor pools are maintained and regulated at the NMJ in living animals remains unknown. Here, we demonstrate that recycled receptors in functional synapses are removed approximately four times faster than pre-existing receptors, and that most removed recycled receptors are replaced by new recycled ones. In denervated NMJs, the recycling of AChRs is significantly depressed and their removal rate increased, whereas direct muscle stimulation prevents their loss. Furthermore, we show that protein tyrosine phosphatase inhibitors cause the selective accumulation of recycled AChRs in the peri-synaptic membrane without affecting the pre-existing AChR pool. The inhibition of serine/threonine phosphatases, however, has no effect on AChR recycling. These data show that recycled receptors are remarkably dynamic, and suggest a potential role for tyrosine dephosphorylation in the insertion and maintenance of recycled AChRs at the postsynaptic membrane. These findings may provide insights into longterm recycling processes at less accessible synapses in the central nervous system in vivo.

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Section: Proper Localization Of Recycled Receptors Requires Tyrosine mentioning

confidence: 72%

Section: Pharmacologymentioning

confidence: 99%

The dynamics of recycled acetylcholine receptors at the neuromuscular junction in vivo

Bruneau

Akaaboune

2006

Development

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“…1-3), SFKs may be counteracted by tyrosine phosphatases. Phosphatase activity dissolves AChR hot spots in cultured Xenopus myocytes, and some of this activity is triggered by agrin application (Madhavan et al, 2005). The phosphatase Shp-2 is a possible candidate, because blocking Shp-2 increases spontaneous AChR clustering (Madhavan et al, 2005).…”

Section: Sfks Control Achr-cytoskeletal Interactionsmentioning

confidence: 99%

Src-Family Kinases Stabilize the Neuromuscular SynapseIn Vivovia Protein Interactions, Phosphorylation, and Cytoskeletal Linkage of Acetylcholine Receptors

et al. 2005

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Postnatal stabilization and maturation of the postsynaptic membrane are important for development and function of the neuromuscular junction (NMJ), but the underlying mechanisms remain poorly characterized. We examined the role of Src-family kinases (SFKs) in vivo. Electroporation of kinase-inactive Src constructs into soleus muscles of adult mice caused NMJ disassembly: acetylcholine receptor (AChR)-rich areas became fragmented; the topology of nerve terminal, AChRs, and synaptic nuclei was disturbed; and occasionally nerves started to sprout. Electroporation of kinase-overactive Src produced similar but milder effects. We studied the mechanism of SFK action using cultured src

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“…When tyrosine phosphatases are inhibited partially in cultured muscle cells (so that AChRs are not completely immobilized), auto-activation of MuSK and spontaneous AChR clustering are enhanced (17). Moreover, coupling low-level tyrosine phosphatase inhibition with agrin-treatment generates enlarged AChR clusters but does not significantly increase the number of agrin-induced clusters (17). In accord with these findings, following tyrosine phosphatase inhibition, AChR clusters induced in muscle cells by co-cultured nerves or growth factor-coated beads become less discrete, with AChR clusters developing past nerve-or bead-contact boundaries (97) (Fig.…”

Section: Tyrosine Kinases and Phosphatasesmentioning

confidence: 99%

“…One potential candidate is the tyrosine phosphatase Shp2. In cultured muscle cells, Shp2 is expressed at high levels and depleting it can enhance MuSK-dependent AChR clustering (17). Whether Shp2 functions through a negative feedback loop to regulate MuSK and if Shp2 also plays a role in dispersing AChR hot spots are issues that remain to be tested.…”

Section: Tyrosine Kinases and Phosphatasesmentioning

confidence: 99%

Molecular regulation of postsynaptic differentiation at the neuromuscular junction

Madhavan

Peng

2005

IUBMB Life (International Union of Biochemistry and Molecular B

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SummaryThe neuromuscular junction (NMJ) is a synapse that develops between a motor neuron and a muscle fiber. A defining feature of NMJ development in vertebrates is the re-distribution of muscle acetylcholine (ACh) receptors (AChRs) following innervation, which generates highdensity AChR clusters at the postsynaptic membrane and disperses aneural AChR clusters formed in muscle before innervation. This process in vivo requires MuSK, a muscle-specific receptor tyrosine kinase that triggers AChR re-distribution when activated; rapsyn, a muscle protein that binds and clusters AChRs; agrin, a nervesecreted heparan-sulfate proteoglycan that activates MuSK; and ACh, a neurotransmitter that stimulates muscle and also disperses aneural AChR clusters. Moreover, in cultured muscle cells, several additional muscle-and nerve-derived molecules induce, mediate or participate in AChR clustering and dispersal. In this review we discuss how regulation of AChR re-distribution by multiple factors ensures aggregation of AChRs exclusively at NMJs.

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Tyrosine phosphatase regulation of MuSK-dependent acetylcholine receptor clustering

Cited by 39 publications

References 50 publications

The dynamics of recycled acetylcholine receptors at the neuromuscular junction in vivo

The dynamics of recycled acetylcholine receptors at the neuromuscular junction in vivo

Src-Family Kinases Stabilize the Neuromuscular SynapseIn Vivovia Protein Interactions, Phosphorylation, and Cytoskeletal Linkage of Acetylcholine Receptors

Molecular regulation of postsynaptic differentiation at the neuromuscular junction

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