Differential targeting of components of the dystrophin complex to the postsynaptic membrane

Marchand, Sophie; Stetzkowski‐Marden, Françoise; Cartaud, Jean

doi:10.1046/j.1460-9568.2001.01373.x

Cited by 18 publications

(27 citation statements)

References 62 publications

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“…It has been proposed that rapsyn and AChRs are co-transported through the secretory pathway to the postsynaptic apparatus in Torpedo electrocytes (20,31). This, together with our observed intracellular rapsyn-AChR complexes (Fig.…”

Section: Neural Agrin Increases the Interaction Of Rapsyn With The Acsupporting

confidence: 86%

Agrin Regulates Rapsyn Interaction with Surface Acetylcholine Receptors, and This Underlies Cytoskeletal Anchoring and Clustering

Moransard¹,

Borges²,

Willmann³

et al. 2003

Journal of Biological Chemistry

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The acetylcholine receptor (AChR)-associated protein rapsyn is essential for neuromuscular synapse formation and clustering of AChRs, but its mode of action remains unclear. We have investigated whether agrin, a key nerve-derived synaptogenic factor, influences rapsyn-AChR interactions and how this affects clustering and cytoskeletal linkage of AChRs. By precipitating AChRs and probing for associated rapsyn, we found that in denervated diaphragm rapsyn associates with synaptic as well as with extrasynaptic AChRs showing that rapsyn interacts with unclustered AChRs in vivo. Interestingly, synaptic AChRs are associated with more rapsyn suggesting that clustering of AChRs may require increased interaction with rapsyn. In similar experiments in cultured myotubes, rapsyn interacted with intracellular AChRs and with unclustered AChRs at the cell surface, although surface interactions are much more prominent. Remarkably, agrin induces recruitment of additional rapsyn to surface AChRs and clustering of AChRs independently of the secretory pathway. This agrin-induced increase in rapsyn-AChR interaction strongly correlates with clustering, because staurosporine and herbimycin blocked both the increase and clustering. Conversely, laminin and calcium induced both increased rapsynAChR interaction and AChR clustering. Finally, time course experiments revealed that the agrin-induced increase occurs with AChRs that become cytoskeletally linked, and that this precedes receptor clustering. Thus, we propose that neural agrin controls postsynaptic aggregation of the AChR by enhancing rapsyn interaction with surface AChRs and inducing cytoskeletal anchoring and that this is an important precursor step for AChR clustering.

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Section: Neural Agrin Increases the Interaction Of Rapsyn With The Acsupporting

confidence: 86%

Agrin Regulates Rapsyn Interaction with Surface Acetylcholine Receptors, and This Underlies Cytoskeletal Anchoring and Clustering

Moransard¹,

Borges²,

Willmann³

et al. 2003

Journal of Biological Chemistry

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“…The notion that GlyR could associate with gephyrin as it is transported from the TGN to the plasma membrane is comparable with that of the association of rapsyn and components of the dystrophin-associated complex with AChR, as suggested by their colocalization in post-Golgi vesicles (Marchand et al, 2000(Marchand et al, , 2001. Although the direct association of these molecules with intracellular AChR was not demonstrated, these reports support the notion that elements of the neuromuscular junction are delivered to the plasma membrane as preassembled complexes .…”

Section: Toward a Preconstruction Of The Postsynaptic Membranessupporting

confidence: 66%

Intracellular Association of Glycine Receptor with Gephyrin Increases Its Plasma Membrane Accumulation Rate

Hanus

Vannier²,

Triller³

2004

J. Neurosci.

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Gephyrin, a tubulin-binding protein, is the core of inhibitory postsynaptic scaffolds stabilizing glycine receptors (GlyRs) and/or GABA A receptors. Previous ultrastructural studies in vivo and in vitro have reported a localization of gephyrin to intracellular cisternas during development or after glycinergic denervation (Seitanidou et al., 1992; Colin et al., 1996, 1998). These data were compatible with a traffic of this cytoplasmic, but membrane-associated, protein together with membrane proteins such as GlyR after exocytosis and/or endocytosis pathways. We have now investigated the consequences of a GlyR-gephyrin interaction on the localization and the dynamics of these two molecules in African green monkey kidney cells (COS-7) cells and in neurons transfected with green fluorescent protein-taggedgephyrin and myc-tagged GlyR ␣ 1 subunits. In these experiments, myc-tagged GlyR ␣ 1 contained, or did not contain, the gephyrinbinding sequence (␤gb) of the GlyR ␤ subunit. We report here that GlyR-gephyrin interaction localizes gephyrin to GlyR-containing organelles. Videomicroscopy and nocodazole treatment indicate that the movements of these vesicles are microtubule dependent. Expressing GlyR ␣ 1 with a thrombin cleavage site between the myc-tag and the N terminal of the GlyR ␣ 1 subunit (Rosenberg et al., 2001) allowed monitoring of newly inserted receptors in the cell surface. Using temperature changes to block GlyR in, and then release it from, the trans-Golgi network, we show that gephyrin accelerates the accumulation of GlyR at the cell surface. Therefore, our data strongly suggest that some GlyR clusters are associated with gephyrin on their way to the cell surface and that this association increases the accumulation of GlyR at the plasma membrane.

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“…The intracellular accumulation of the syntrophins suggests that these proteins are targeted to the muscle membrane via a different mechanism than that used by the rest of the DAPC. Indeed, previous work has indeed shown that dystrophin and syntrophin take different routes during targeting to the membrane (32). Syntrophins are transported in post-Golgi vesicles that exocytose to fuse with the membrane, while dystrophin becomes directly associated with the sarcolemma following synthesis.…”

Section: Discussionmentioning

confidence: 99%

Biglycan regulates the expression and sarcolemmal localization of dystrobrevin, syntrophin, and nNOS

Mercado¹,

Amenta²,

Hagiwara³

et al. 2006

FASEB j.

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The dystrophin associated protein complex (DAPC) provides a linkage between the cytoskeleton and the extracellular matrix and is also a scaffold for a host of signaling molecules. The constituents of the DAPC must be targeted to the sarcolemma in order to properly function. Biglycan is an extracellular matrix molecule that associates with the DAPC. Here, we show that biglycan null mice exhibit a mild dystrophic phenotype and display a selective reduction in the localization of α-dystrobrevin -1 and -2, α-and β1-syntrophin, and nNOS at the sarcolemma. Purified biglycan induces nNOS redistribution to the plasma membrane in cultured muscle cells. Biglycan protein injected into muscle becomes stably associated with the sarcolemma and extracellular matrix for at least two weeks. This injected biglycan restores the sarcolemmal expression of α-dystrobrevin-1 and -2, and β1-and β2-syntrophin in biglycan null mice. We conclude that biglycan is important for the maintenance of muscle cell integrity and plays a direct role in regulating the expression and sarcolemmal localization of the intracellular signaling proteins dystrobrevin-1 and -2, α-and β1-syntrophin and nNOS.

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Differential targeting of components of the dystrophin complex to the postsynaptic membrane

Cited by 18 publications

References 62 publications

Agrin Regulates Rapsyn Interaction with Surface Acetylcholine Receptors, and This Underlies Cytoskeletal Anchoring and Clustering

Agrin Regulates Rapsyn Interaction with Surface Acetylcholine Receptors, and This Underlies Cytoskeletal Anchoring and Clustering

Intracellular Association of Glycine Receptor with Gephyrin Increases Its Plasma Membrane Accumulation Rate

Biglycan regulates the expression and sarcolemmal localization of dystrobrevin, syntrophin, and nNOS

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