Abstract
Neuromuscular synapse formation is brought about by a complex bi-directional exchange of information between the innervating motor neuron and its target skeletal muscle fiber. Agrin, a heparin sulfate proteoglycan, is released from the motor nerve terminal to activate its muscle-specific kinase (MuSK) receptor that leads to a second messenger cascade requiring rapsyn to ultimately bring about AChR clustering in the muscle membrane. Rapsyn performs many functions in skeletal muscle. First, rapsyn and AChRs co-target to the postsynatic apparatus. Second, rapsyn may self associate to stabilize and promote AChR clustering. Third, rapsyn is essential for AChR cluster formation. Fourth, rapsyn is required to transduce the agrin-evoked MuSK phosphorylation signal to AChRs. Finally, rapsyn links AChRs to the utrophin-associated complex, which appears to be required for AChR stabilization as well as maturation of the neuromuscular junction. Proteins within the utrophin-associated complex such as α-dystrobrevin and α-syntrophin are also important for signaling events that affect neuromuscular synapse stability and function. Here we review our current understanding of the role of the postsynaptic-submembrane machinery involving rapsyn and the utrophin-associated complex at the neuromuscular synapse. In addition we briefly review how these studies of the neuromuscular junction relate to GABAergic and glycinergic synapses in the CNS.
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ADAMS, M. E., BUTLER, M. H., DWYER, T. M., PETERS, M. F., MURNANE, A. A. & FROEHNER, S. C. (1993) Two forms of mouse syntrophin, a 58 kd dystrophinassociated protein, differ in primary structure and tissue distribution. Neuron 11(3), 53–540.
ADAMS, M. E., DWYER, T. M., DOWLER, L. L., WHITE, R. A. & FROEHNER, S. C. (1995) Mouse alpha 1-and beta 2-syntrophin gene structure, chromosome localization, and homology with a discs large domain. Journal of Biological Chemistry 270(43), 2585–25865.
ADAMS, M. E., KRAMARCY, N., KRALL, S. P., ROSSI, S. G., ROTUNDO, R. L., SEALOCK, R. & FROEHNER, S. C. (2000) Absence of alpha-syntrophin leads to structurally aberrant neuromuscular synapses deficient in utrophin. Journal of Cell Biology 150(6), 138–1398.
ADAMS, M. E., MUELLER, H. A. & FROEHNER, S. C. (2001) In vivo requirement of the alpha-syntrophin PDZ domain for the sarcolemmal localization of nNOS and aquaporin-4. Journal of Cell Biology 155(1), 11–122.
AHN, A. H. & KUNKEL, L. M. (1995) Syntrophin binds to an alternatively spliced exon of dystrophin. Journal of Cell Biology 128(3), 36–371.
AHN, A. H., YOSHIDA, M., ANDERSON, M. S., FEENER, C. A., SELIG, S., HAGIWARA, Y., OZAWA, E. & KUNKEL, L. M. (1994) Cloning of human basic A1, a distinct 59-kDa dystrophin-associated protein encoded on chromosome 8q23-24. Proceedings of the National Academy of Sciences USA 91(10), 444–4450.
AKAABOUNE, M., GRADY, R. M., TURNEY, S., SANES, J. R. & LICHTMAN, J. W. (2002) Neurotransmitter receptor dynamics studied in vivo by reversible photounbinding of fluorescent ligands. Neuron 34(6), 86– 876.
ALBRECHT, D. E. & FROEHNER, S. C. (2002) Syntrophins and dystrobrevins: Defining the dystrophin scaffold at synapses. Neurosignals 11(3), 12–129.
ANDERSON, M. J. & FAMBROUGH, D. M. (1983) Aggregates of acetylcholine receptors are associated with plaques of a basal lamina heparan sulfate proteoglycan on the surface of skeletal muscle fibers. Journal of Cell Biology 97(5 Pt 1), 139–1411.
ANTONY, C., HUCHET, M., CHANGEUX, J. P. & CARTAUD, J. (1995) Developmental regulation ofmembrane traffic organization during synaptogenesis in mouse diaphragm muscle. Journal of Cell Biology 130(4), 95–968.
APEL, E. D., GLASS, D. J., MOSCOSO, L. M., YANCOPOULOS, G. D. & SANES, J. R. (1997) Rapsyn is required for MuSK signaling and recruits synaptic components to a MuSK-containing scaffold. Neuron 18(4), 62–635.
APEL, E. D. & MERLIE, J. P. (1995) Assembly of the postsynaptic apparatus. Current Opinion in Neurobiology 5(1), 6–67.
APEL, E. D., ROBERDS, S. L., CAMPBELL, K. P. & MERLIE, J. P. (1995) Rapsyn may function as a link between the acetylcholine receptor and the agrin-binding dystrophin-associated glycoprotein complex. Neuron 15(1), 11–126.
ARIKAWA-HIRASAWA, E., ROSSI, S. G., ROTUNDO, R. L. & YAMADA, Y. (2002) Absence of acetylcholinesterase at the neuromuscular junctions of perlecan-null mice. Nature Neuroscience 5(2), 11–123.
BANKS, G. B., CHOY, P. T., LAVIDIS, N. A. & NOAKES, P. G. (2003) Neuromuscular synapses mediate motor axon branching and motoneuron survival during the embryonic period of programmed cell death. Developmental Biology 257(1), 7–84.
BARTOLI, M., RAMARAO, M. K. & COHEN, J. B. (2001) Interactions of the rapsyn RING-H2 domain with dystroglycan. Journal of Biological Chemistry 276(27), 2491–24917.
BAYNE, E. K., ANDERSON, M. J. & FAMBROUGH, D. M. (1984) Extracellular matrix organization in developing muscle: Correlation with acetylcholine receptor aggregates. Journal of Cell Biology 99(4 Pt 1), 148–1501.
BEWICK, G. S., NICHOLSON, L. V., YOUNG, C., O'DONNELL, E. & SLATER, C. R. (1992) Different distributions of dystrophin and related proteins at nervemuscle junctions. Neuroreport 3(10), 85–860.
BEZAKOVA, G. & BLOCH, R. J. (1998) The zinc finger domain of the 43-kDa receptor-associated protein, rapsyn: Role in acetylcholine receptor clustering. Molecular and Cellular Neuroscience 11(5/6), 27–288.
BEZAKOVA, G. & LOMO, T. (2001) Muscle activity and muscle agrin regulate the organization of cytoskeletal proteins and attached acetylcholine receptor (AchR) aggregates in skeletal muscle fibers. Journal of Cell Biology 153(7), 145–1463.
BLAKE, D. J., HAWKES, R., BENSON, M. A. & BEESLEY, P. W. (1999) Different dystrophin-like complexes are expressed in neurons and glia. Journal of Cell Biology 147(3), 64–658.
BLAKE, D. J., NAWROTZKI, R., PETERS, M. F., FROEHNER, S. C. & DAVIES, K. E. (1996) Isoform diversity of dystrobrevin, the murine 87-kDa postsynaptic protein. Journal of Biological Chemistry 271(13), 780– 7810.
BORGES, L. S. & FERNS, M. (2001) Agrin-induced phosphorylation of the acetylcholine receptor regulates cytoskeletal anchoring and clustering. Journal of Cell Biology 153(1), –12.
BOWE, M. A., DEYST, K. A., LESZYK, J. D. & FALLON, J. R. (1994) Identification and purification of an agrin receptor from Torpedo postsynaptic membranes: A heteromeric complex related to the dystroglycans. Neuron 12(5), 117–1180.
BRENMAN, J. E., CHAO, D. S., GEE, S. H., MCGEE, A. W., CRAVEN, S. E., SANTILLANO, D. R., WU, Z., HUANG, F., XIA, H., PETERS, M. F., FROEHNER, S. C. & BREDT, D. S. (1996) Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and alpha1-syntrophin mediated by PDZ domains. Cell 84(5), 75–767.
BRIDGMAN, P. C., CARR, C., PEDERSEN, S. E. & COHEN, J. B. (1987) Visualization of the cytoplasmic surface of Torpedo postsynaptic membranes by freezeetch and immunoelectron microscopy. Journal of Cell Biology 105(4), 182–1846.
BRUNIG, I., SUTER, A., KNUESEL, I., LUSCHER, B. & FRITSCHY, J. M. (2002) GABAergic terminals are required for postsynaptic clustering of dystrophin but not of GABA(A) receptors and gephyrin. Journal of Neuroscience 22(12), 480–4813.
BURDEN, S. J. (1993) Synapse-specific gene expression. Trends in Genetics 9(1), 1–16.
BURDEN, S. J., DEPALMA, R. L. & GOTTESMAN, G. S. (1983) Crosslinking of proteins in acetylcholine receptorrich membranes: Association between the beta-subunit and the 43 kd subsynaptic protein. Cell. 35, 68–692.
BURGESS, R. W., DICKMAN, D. K., NUNEZ, L., GLASS, D. J. & SANES, J. R. (2002) Mapping sites responsible for interactions of agrin with neurons. Journal of Neurochemistry 83(2), 27–284.
BURGESS, R. W., SKARNES, W. C. & SANES, J. R. (2000) Agrin isoforms with distinct amino termini: Differential expression, localization, and function. Journal of Cell Biology 151(1), 4–52.
BURKIN, D. J., GU, M., HODGES, B. L., CAMPANELLI, J. T. & KAUFMAN, S. J. (1998) A functional role for specific spliced variants of the alpha7beta1 integrin in acetylcholine receptor clustering. Journal of Cell Biology. 143, 106–1075.
BYERS, T. J., KUNKEL, L. M. & WATKINS, S. C. (1991) The subcellular distribution of dystrophin in mouse skeletal, cardiac, and smooth muscle. Journal of Cell Biology 115(2), 41–421.
CAMPANELLI, J. T., GAYER, G. G. & SCHELLER, R. H. (1996) Alternative RNA splicing that determines agrin activity regulates binding to heparin and alphadystroglycan. Development 122(5), 166–1672.
CAMPANELLI, J. T., ROBERDS, S. L., CAMPBELL, K. P. & SCHELLER, R. H. (1994) A role for dystrophinassociated glycoproteins and utrophin in agrin-induced AChR clustering. Cell 77(5), 66–674.
CAMUS, G., LUDOSKY, M. A., BIGNAMI, F., MARCHAND, S., CARTAUD, J. & CARTAUD, A. (1999) Developmental regulation of tyrosine phosphorylation of the nicotinic acetylcholine receptor in Torpedo electrocyte. Molecular and Cellular Neuroscience 13(1), 6–78.
CARTAUD, A., COUTANT, S., PETRUCCI, T. C. & CARTAUD, J. (1998) Evidence for in situ and in vitro association between beta-dystroglycan and the subsynaptic 43K rapsyn protein. Consequence for acetylcholine receptor clustering at the synapse. Journal of Biological Chemistry 273(18), 1132–11326.
CHOCKALINGAM, P. S., GEE, S. H. & JARRETT, H. W. (1999) Pleckstrin homology domain 1 of mouse alpha 1-syntrophin binds phosphatidylinositol 4,5-bisphosphate. Biochemistry 38(17), 559–5602.
CHUNG, W. & CAMPANELLI, J. T. (1999) WW and EF hand domains of dystrophin-family proteins mediate dystroglycan binding. Molecular Cell Biology Research Communications 2(3), 16–171.
COLLEDGE, M. & FROEHNER, S. C. (1998) To muster a cluster: Anchoring neurotransmitter receptors at synapses. Proceedings of the National Academy of Sciences USA 95(7), 334–3343.
COTE, P. D., MOUKHLES, H. & CARBONETTO, S. (2002) Dystroglycan is not required for localization of dystrophin, syntrophin, and neuronal nitric-oxide synthase at the sarcolemma but regulates integrin alpha 7B expression and caveolin-3 distribution. Journal of Biological Chemistry 277(7), 467–4679.
COTE, P. D., MOUKHLES, H., LINDENBAUM, M. & CARBONETTO, S. (1999) Chimaeric mice deficient in dystroglycans develop muscular dystrophy and have disrupted myoneural synapses. Nature Genetics 23(3), 33–342.
DAI, Z., SCOTLAND, P. B., FROEHNER, S. C. & PENG, H. B. (1996) Association of phosphotyrosine with rapsyn expression in Xenopus embryonic cells. Neuroreport 7(2), 65–661.
DANIELS, M. P., KRIKORIAN, J. G., OLEK, A. J. & BLOCH, R. J. (1990) Association of cytoskeletal proteins with newly formed acetylcholine receptor aggregates induced by embryonic brain extract. Experimental Cell Research 186(1), 9–108.
DECHIARA, T. M., BOWEN, D. C., VALENZUELA, D. M., SIMMONS, M. V., POUEYMIROU, W. T., THOMAS, S., KINETZ, E., COMPTON, D. L., ROJAS, E., PARK, J. S., SMITH, C., DISTEFANO, P. S., GLASS, D. J., BURDEN, S. J. & YANCOPOULOS, G. D. (1996) The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo. Cell 85(4), 50–512.
DECONINCK, A. E., POTTER, A. C., TINSLEY, J. M., WOOD, S. J., VATER, R., YOUNG, C., METZINGER, L., VINCENT, A., SLATER, C. R. & DAVIES, K. E. (1997a) Postsynaptic abnormalities at the neuromuscular junctions of utrophin-deficient mice. Journal of Cell Biology 136(4), 88–894.
DECONINCK, A. E., RAFAEL, J. A., SKINNER, J. A., BROWN, S. C., POTTER, A. C., METZINGER, L., WATT, D. J., DICKSON, J. G., TINSLEY, J. M. & DAVIES, K. E. (1997b) Utrophin-dystrophin-deficient mice as a model for Duchenne muscular dystrophy. Cell 90(4), 71–727.
DUCLOS, F., STRAUB, V., MOORE, S. A., VENZKE, D. P., HRSTKA, R. F., CROSBIE, R. H., DURBEEJ, M., LEBAKKEN, C. S., ETTINGER, A. J., VAN DER MEULEN, J., HOLT, K. H., LIM, L. E., SANES, J. R., DAVIDSON, B. L., FAULKNER, J. A., WILLIAMSON, R. & CAMPBELL, K. P. (1998) Progressive muscular dystrophy in alphasarcoglycan-deficient mice. Journal of Cell Biology 142(6), 146–1471.
DUNNE, V. & MASELLI, R. A. (2003) Identification of pathogenic mutations in the human rapsyn gene. Journal of Human Genetics 48, 20–207.
ENGEL, A. G., OHNO, K. & SINE, S. M. (2002) The spectrum of congenital myasthenic syndromes. Molecular Neurobiology 26(2/3), 34–367.
ENGEL, A. G., OHNO, K. & SINE, S. M. (2003a) Congenital myasthenic syndromes: Progress over the past decade. Muscle Nerve. 27, –25.
ENGEL, A. G., OHNO, K. & SINE, S. M. (2003b) Neurological diseases: Sleuthing molecular targets for neurological diseases at the neuromuscular junction. Nature Reviews Neuroscience. 4, 33–352.
ESSRICH, C., LOREZ, M., BENSON, J. A., FRITSCHY, J. M. & LUSCHER, B. (1998) Postsynaptic clustering of major GABAA receptor subtypes requires the gamma 2 subunit and gephyrin. Nature Neuroscience. 1, 56–571.
FALLON, J. R. & HALL, Z. W. (1994) Building synapses: Agrin and dystroglycan stick together. Trends in Neuroscience 17(11), 46–473.
FENG, G., TINTRUP, H., KIRSCH, J., NICHOL, M. C., KUHSE, J., BETZ, H. & SANES, J. R. (1998) Dual requirement for gephyrin in glycine receptor clustering and molybdoenzyme activity. Science 282(5392), 132–1324.
FERNS, M. J., CAMPANELLI, J. T., HOCH, W., SCHELLER, R. H. & HALL, Z. (1993) The ability of agrin to cluster AChRs depends on alternative splicing and on cell surface proteoglycans. Neuron 11(3), 49–502.
FERTUCK, H. C. & SALPETER, M. M. (1974) Localization of acetylcholine receptor by 125I-labeled alphabungarotoxin binding at mouse motor endplates. Proceedings of the National Academy of Sciences USA 71(4), 137–1378.
FINN, A. J., FENG, G. & PENDERGAST, A. M. (2003) Postsynaptic requirement for Abl kinases in assembly of the neuromuscular junction. Nature Neuroscience 6(7), 71–723.
FRAIL, D. E., MCLAUGHLIN, L. L., MUDD, J. & MERLIE, J. P. (1988) Identification of the mouse muscle 43,000-dalton acetylcholine receptor-associated protein (RAPsyn) by cDNA cloning. Journal of Biological Chemistry 263(30), 1560–15607.
FRIEDMAN, H. V., BRESLER, T., GARNER, C. C. & ZIV, N. E. (2000) Assembly of new individual excitatory synapses: Time course and temporal order of synaptic molecule recruitment. Neuron. 27, 5–69.
FROEHNER, S. C. (1991) The submembrane machinery for nicotinic acetylcholine receptor clustering. Journal of Cell Biology 114(1), –7.
FROEHNER, S. C., LUETJE, C. W., SCOTLAND, P. B. & PATRICK, J. (1990) The postsynaptic 43K protein clusters muscle nicotinic acetylcholine receptors in Xenopus oocytes. Neuron 5(4), 40–410.
FUHRER, C., SUGIYAMA, J. E., TAYLOR, R. G. & HALL, Z. W. (1997). Association of muscle-specific kinase MuSK with the acetylcholine receptor in mammalian muscle. The European Molecular Biology Organization Journal. 16, 495–4960.
FUHRER, C., GAUTAM, M., SUGIYAMA, J. E. & HALL, Z. W. (1999) Roles of rapsyn and agrin in interaction of postsynaptic proteins with acetylcholine receptors. Journal of Neuroscience 19(15), 640–6416.
FUHRMANN, J. C., KINS, S., ROSTAING, P., EL FAR, O., KIRSCH, J., SHENG, M., TRILLER, A., BETZ, H. & KNEUSSEL, M. (2002) Gephyrin interacts with Dynein light chains 1 and 2, components of motor protein complexes. Journal of Neuroscience 22(13), 539–5402.
GARCIA, R. A., VASUDEVAN, K. & BUONANNO, A. (2000) The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses. Proceedings of the National Academy of Sciences USA 97(7), 359–3601.
GAUTAM, M., NOAKES, P. G., MOSCOSO, L., RUPP, F., SCHELLER, R. H., MERLIE, J. P. & SANES, J. R. (1996) Defective neuromuscular synaptogenesis in agrindeficient mutant mice. Cell 85(4), 52–535.
GAUTAM, M., NOAKES, P. G., MUDD, J., NICHOL, M., CHU, G. C., SANES, J. R. & MERLIE, J. P. (1995) Failure of postsynaptic specialization to develop at neuromuscular junctions of rapsyn-deficient mice. Nature 377(6546), 23–236.
GEE, S. H., MADHAVAN, R., LEVINSON, S. R., CALDWELL, J. H., SEALOCK, R. & FROEHNER, S. C. (1998) Interaction of muscle and brain sodium channels with multiple members of the syntrophin family of dystrophin-associated proteins. Journal of Neuroscience 18(1), 12–137.
GEE, S. H., MONTANARO, F., LINDENBAUM, M. H. & CARBONETTO, S. (1994) Dystroglycan-alpha, a dystrophin-associated glycoprotein, is a functional agrin receptor. Cell 77(5), 67–686.
GILLESPIE, S. K., BALASUBRAMANIAN, S., FUNG, E. T. & HUGANIR, R. L. (1996) Rapsyn clusters and activates the synapse-specific receptor tyrosine kinase MuSK. Neuron 16(5), 95–962.
GRADY, R. M., AKAABOUNE, M., COHEN, A. L., MAIMONE, M. M., LICHTMAN, J. W. & SANES, J. R. (2003) Tyrosine-phosphorylated and nonphosphorylated isoforms of alpha-dystrobrevin: Roles in skeletal muscle and its neuromuscular and myotendinous junctions. Journal of Cell Biology 160(5), 74–752.
GRADY, R. M., GRANGE, R. W., LAU, K. S., MAIMONE, M. M., NICHOL, M. C., STULL, J. T. & SANES, J. R. (1999) Role for alpha-dystrobrevin in the pathogenesis of dystrophin-dependent muscular dystrophies. Nature Cell Biology 1(4), 21–220.
GRADY, R. M., MERLIE, J. P. & SANES, J. R. (1997a) Subtle neuromuscular defects in utrophin-deficient mice. Journal of Cell Biology 136(4), 87–882.
GRADY, R. M., TENG, H., NICHOL, M. C., CUNNINGHAM, J. C., WILKINSON, R. S. & SANES, J. R. (1997b) Skeletal and cardiac myopathies in mice lacking utrophin and dystrophin: A model for Duchenne muscular dystrophy. Cell 90(4), 72–738.
GRADY, R. M., ZHOU, H., CUNNINGHAM, J. M., HENRY, M. D., CAMPBELL, K. P. & SANES, J. R. (2000) Maturation and maintenance of the neuromuscular synapse: Genetic evidence for roles of the dystrophin—glycoprotein complex. Neuron 25(2), 27–293.
GROSSKREUTZ, Y., BETZ, H. & KNEUSSEL, M. (2003) Rescue of molybdenum cofactor biosynthesis in gephyrin-deficient mice by a Cnx1 transgene. Biochemical and Biophysical Research Communications 301(2), 45– 455.
HACK, A. A., LY, C. T., JIANG, F., CLENDENIN, C. J., SIGRIST, K. S., WOLLMANN, R. L. & MCNALLY, E. M. (1998) Gamma-sarcoglycan deficiency leads to muscle membrane defects and apoptosis independent of dystrophin. Journal of Cell Biology 142(5), 127–1287.
HAGIWARA, H. & FALLON, J. R. (2001) Shaping membrane architecture: Agrins in and out of the synapse. Journal of Cell Biology 153(7), F3–F42.
HAN, H., NOAKES, P. G. & PHILLIPS, W. D. (1999) Overexpression of rapsyn inhibits agrin-induced acetylcholine receptor clustering in muscle cells. Journal of Neurocytology 28(9), 76–775.
HASEGAWA, M., CUENDA, A., SPILLANTINI, M. G., THOMAS, G. M., BUEE SCHERRER, V., COHEN, P. & GOEDERT, M. (1999) Stress-activated protein kinase-3 interacts with the PDZ domain of alpha1-syntrophin. A mechanism for specific substrate recognition. Journal of Biological Chemistry 274(18), 1262–12631.
HEATHCOTE, R. D., EKMAN, J. M., CAMPBELL, K. P. & GODFREY, E. W. (2000) Dystroglycan overexpression in vivo alters acetylcholine receptor aggregation at the neuromuscular junction. Developmental Biology 227(2), 59–605.
HERBST, R., AVETISOVA, E. & BURDEN, S. J. (2002) Restoration of synapse formation in Musk mutant mice expressing a Musk/Trk chimeric receptor. Development 129(23), 544–5460.
HERBST, R. & BURDEN, S. J. (2000) The juxtamembrane region of MuSK has a critical role in agrin-mediated signaling. The European Molecular Biology Organization Journal 19(1), 6–77.
HOLZFEIND, P. J., AMBROSE, H. J., NEWEY, S. E., NAWROTZKI, R. A., BLAKE, D. J. & DAVIES, K. E. (1999) Tissue-selective expression of alpha-dystrobrevin is determined by multiple promoters. Journal of Biological Chemistry 274(10), 625–6258.
HOPF, C. & HOCH, W. (1996) Agrin binding to alphadystroglycan. Domains of agrin necessary to induce acetylcholine receptor clustering are overlapping but not identical to the alpha-dystroglycan-binding region. Journal of Biological Chemistry 271(9), 523–5236.
HUH, K. H. & FUHRER, C. (2002) Clustering of nicotinic acetylcholine receptors: From the neuromuscular junction to interneuronal synapses. Molecular Neurobiology 25, 7–112.
IOZZO, R. V., COHEN, I. R., GRASSEL, S. & MURDOCH, A. D. (1994) The biology of perlecan: The multifaceted heparan sulphate proteoglycan of basement membranes and pericellular matrices. Biochemical Journal 302(Pt 3), 62–639.
IWATA, Y., PAN, Y., YOSHIDA, T., HANADA, H. & SHIGEKAWA, M. (1998) Alpha1-syntrophin has distinct binding sites for actin and calmodulin. Federation of European Biochemical Societies Letters 423(2), 17– 177.
JACOBSON, C., COTE, P. D., ROSSI, S. G., ROTUNDO, R. L. & CARBONETTO, S. (2001) The dystroglycan complex is necessary for stabilization of acetylcholine receptor clusters at neuromuscular junctions and formation of the synaptic basement membrane. Journal of Cell Biology 152(3), 43–450.
JASMIN, B. J., ANTONY, C., CHANGEUX, J. P. & CARTAUD, J. (1995) Nerve-dependent plasticity of the Golgi complex in skeletal muscle fibres: Compartmentalization within the subneural sarcoplasm. Eur Journal of Neuroscience 7(3), 47–479.
JASMIN, B. J., CARTAUD, J., BORNENS, M. & CHANGEUX, J. P. (1989) Golgi apparatus in chick skeletal muscle: Changes in its distribution during end plate development and after denervation. Proceedings of the National Academy of Sciences USA 86(18), 721–7222.
JASMIN, B. J., CHANGEUX, J. P. & CARTAUD, J. (1990) Compartmentalization of cold-stable and acetylated microtubules in the subsynaptic domain of chick skeletal muscle fibre. Nature 344(6267), 67–675.
JO, S. A., ZHU, X., MARCHIONNI, M. A. & BURDEN, S. J. (1995) Neuregulins are concentrated at nerve-muscle synapses and activate ACh-receptor gene expression. Nature 373(6510), 15–161.
KACHINSKY, A. M., FROEHNER, S. C. & MILGRAM, S. L. (1999) A PDZ-containing scaffold related to the dystrophin complex at the basolateral membrane of epithelial cells. Journal of Cell Biology 145(2), 39–402.
KAHL, J. & CAMPANELLI, J. T. (2003) A role for the juxtamembrane domain of beta-dystroglycan in agrininduced acetylcholine receptor clustering. Journal of Neuroscience 23(2), 39–402.
KAMEYA, S., MIYAGOE, Y., NONAKA, I., IKEMOTO, T., ENDO, M., HANAOKA, K., NABESHIMA, Y. & TAKEDA, S. (1999) alpha1-syntrophin gene disruption results in the absence of neuronal-type nitric-oxide synthase at the sarcolemma but does not induce muscle degeneration. Journal of Biological Chemistry 274(4), 219–2200.
KIRSCH, J. & BETZ, H. (1995) The postsynaptic localization of the glycine receptor-associated protein gephyrin is regulated by the cytoskeleton. Journal of Neuroscience 15(6), 414–4156.
KIRSCH, J. & BETZ, H. (1998) Glycine-receptor activation is required for receptor clustering in spinal neurons. Nature 392(6677), 71–720.
KIRSCH, J., KUHSE, J. & BETZ, H. (1995) Targeting of glycine receptor subunits to gephyrin-rich domains in transfected human embryonic kidney cells. Molecular and Cellular Neuroscience 6(5), 45–461.
KIRSCH, J., WOLTERS, I., TRILLER, A. & BETZ, H. (1993) Gephyrin antisense oligonucleotides prevent glycine receptor clustering in spinal neurons. Nature 366(6457), 74–748.
KNEUSSEL, M., BRANDSTATTER, J. H., GASNIER, B., FENG, G., SANES, J. R. & BETZ, H. (2001) Gephyrinindependent clustering of postsynaptic GABA(A) receptor subtypes. Molecular and Cellular Neuroscience 17(6), 97–982.
KNEUSSEL, M., BRANDSTATTER, J. H., LAUBE, B., STAHL, S., MULLER, U. & BETZ, H. (1999) Loss of postsynaptic GABA(A) receptor clustering in gephyrindeficient mice. Journal of Neuroscience 19(21), 928–9297.
KNUESEL, I., MASTROCOLA, M., ZUELLIG, R. A., BORNHAUSER, B., SCHAUB, M. C. & FRITSCHY, J. M. (1999) Short communication: Altered synaptic clustering of GABAA receptors in mice lacking dystrophin (mdx mice). European Journal of Neuroscience 11(12), 445–4462.
KNUESEL, I., ZUELLIG, R. A., SCHAUB, M. C. & FRITSCHY, J. M. (2001) Alterations in dystrophin and utrophin expression parallel the reorganization of GABAergic synapses in a mouse model of temporal lobe epilepsy. European Journal of Neuroscience 13(6), 111–1124.
KOPTA, C. & STEINBACH, J. H. (1994) Comparison of mammalian adult and fetal nicotinic acetylcholine receptors stably expressed in fibroblasts. Journal of Neuroscience 14(6), 392–3933.
KRAMARCY, N. R. & SEALOCK, R. (2000) Syntrophin isoforms at the neuromuscular junction: Developmental time course and differential localization. Molecular and Cellular Neuroscience 15(3), 26–274.
KRIKORIAN, J. G. & BLOCH, R. J. (1992) Treatments that extract the 43K protein from acetylcholine receptor clusters modify the conformation of cytoplasmic domains of all subunits of the receptor. Journal of Biological Chemistry 267(13), 911–9128.
LAROCHELLE, W. J. & FROEHNER, S. C. (1986) Determination of the tissue distributions and relative concentrations of the postsynaptic 43-kDa protein and the acetylcholine receptor in Torpedo. Journal of Biological Chemistry 261(12), 527–5274.
LAROCHELLE, W. J. & FROEHNER, S. C. (1987) Comparison of the postsynaptic 43-kDa protein from muscle cells that differ in acetylcholine receptor clustering activity. Journal of Biological Chemistry 262(17), 819–8195.
LAROCHELLE, W. J., RALSTON, E., FORSAYETH, J. R., FROEHNER, S. C. & HALL, Z. W. (1989) Clusters of 43-kDa protein are absent from genetic variants of C2 muscle cells with reduced acetylcholine receptor expression. Developmental Biology. 132, 13–138.
LEVI, S., GRADY, R. M., HENRY, M. D., CAMPBELL, K. P., SANES, J. R. & CRAIG, A. M. (2002) Dystroglycan is selectively associated with inhibitory GABAergic synapses but is dispensable for their differentiation. Journal of Neuroscience 22(11), 427–4285.
LIN, W., BURGESS, R. W., DOMINGUEZ, B., PFAFF, S. L., SANES, J. R. & LEE, K. F. (2001) Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse. Nature 410(6832), 105– 1064.
LOVE, D. R., HILL, D. F., DICKSON, G., SPURR, N. K., BYTH, B. C., MARSDEN, R. F., WALSH, F. S., EDWARDS, Y. H. & DAVIES, K. E. (1989) An autosomal transcript in skeletal muscle with homology to dystrophin. Nature 339(6219), 5–58.
LUMENG, C., PHELPS, S., CRAWFORD, G. E., WALDEN, P. D., BARALD, K. & CHAMBERLAIN, J. S. (1999) Interactions between beta 2-syntrophin and a family of microtubule-associated serine/threonine kinases. Nature Neuroscience 2(7), 61–617.
LUPAS, A. (1996) Coiled coils:Newstructures and new functions. Trends in Biochemical Sciences 21(10), 37–382.
MADHAVAN, R. & JARRETT, H. W. (1995) Interactions between dystrophin glycoprotein complex proteins. Biochemistry 34(38), 1220–12209.
MAIMONE, M. M. & ENIGK, R. E. (1999) The intracellular domain of the nicotinic acetylcholine receptor alpha subunit mediates its coclustering with rapsyn. Molecular and Cellular Neuroscience 14(4/5), 34–354.
MAIMONE, M. M. & MERLIE, J. P. (1993) Interaction of the 43 kd postsynaptic protein with all subunits of the muscle nicotinic acetylcholine receptor. Neuron 11(1), 5–66.
MARANGI, P. A., FORSAYETH, J. R., MITTAUD, P., ERB-VÖGTLI, S., BLAKE, D. J., MORANSARD, M., SANDER, A. & FUHRER, C. (2001) Acetylcholine receptors are required for agrin-induced clustering of postsynaptic proteins. The European Molecular Biology Organization Journal 20, 706–7073.
MARANGI, P.A., WIELAND, S. T. & FUHRER, C. (2002) Laminin-1 redistributes postsynaptic proteins and requires rapsyn, tyrosine phosphorylation, and Src and Fyn to stably cluster acetylcholine receptors. Journal of Cell Biology 157, 88–895.
MARCHAND, S., BIGNAMI, F., STETZKOWSKIMARDEN, F. & CARTAUD, J. (2000) The myristoylated protein rapsyn is cotargeted with the nicotinic acetylcholine receptor to the postsynaptic membrane via the exocytic pathway. Journal of Neuroscience 20(2), 52–528.
MARCHAND, S. & CARTAUD, J. (2002) Targeted trafficking of neurotransmitter receptors to synaptic sites. Molecular Neurobiology 26(1), 11–135.
MARCHAND, S., DEVILLERS-THIERY, A., PONS, S., CHANGEUX, J. P. & CARTAUD, J. (2002) Rapsyn escorts the nicotinic acetylcholine receptor along the exocytic pathway via association with lipid rafts. Journal of Neuroscience 22(20), 889–8901.
MCMAHAN, U. J. (1990) The agrin hypothesis. Cold Spring Harbor Symposium on Quantitative Biology 55, 40–418.
MITTAUD, P., MARANGI, P. A., ERB-VOGTLI, S. & FUHRER, C. (2001) Agrin-induced activation of acetylcholine receptor-bound Src family kinases requires Rapsyn and correlates with acetylcholine receptor clustering. Journal of Biological Chemistry 276(17), 1450– 14513.
MEYER, G. & WALLACE, B. G. (1998). Recruitment of a nicotinic acetylcholine receptor mutant lacking cytoplasmic tyrosine residues in its beta subunit into agrininduced aggregates. Molecular and Cellular Neuroscience 11, 32–333.
MOHAMED, A. S. & SWOPE, S. L. (1999) Phosphorylation and cytoskeletal anchoring of the acetylcholine receptor Rapsyn and the utrophin/dystrophin-associated complex at synapses 725 by Src class protein-tyrosine kinases. Activation by rapsyn. Journal of Biological Chemistry 274(29), 2052–20539.
MOHAMED, A. S., RIVAS-PLATA, K. A., KRAAS, J. R., SALEH, S. M. & SWOPE, S. L. (2001). Src-class kinases act within the agrin/MuSK pathway to regulate acetylcholine receptor phosphorylation, cytoskeletal anchoring, and clustering. Journal of Neuroscience 21, 380–3818.
MONTANARO, F., GEE, S. H., JACOBSON, C., LINDENBAUM, M. H., FROEHNER, S. C. & CARBONETTO, S. (1998) Laminin and alphadystroglycan mediate acetylcholine receptor aggregation via a MuSK-independent pathway. Journal of Neuroscience 18(4), 125–1260.
MOORE, S. A., SAITO, F., CHEN, J., MICHELE, D. E., HENRY, M. D., MESSING, A., COHN, R. D., ROSSBARTA, S. E., WESTRA, S., WILLIAMSON, R. A., HOSHI, T. & CAMPBELL, K. P. (2002) Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature 418(6896), 42–425.
MORANSARD, M., BORGES, L. S., WILLMANN, R., MARANGI, P. A., BRENNER, H. R., FERNS, M. J. & FUHRER, C. (2003) Agrin regulates rapsyn interaction with surface acetylcholine receptors, and this underlies cytoskeletal anchoring and clustering. Journal of Biological Chemistry 278(9), 735–7359.
MOSCOSO, L. M., MERLIE, J. P. & SANES, J. R. (1995) N-CAM, 43K-rapsyn, and S-laminin mRNAs are concentrated at synaptic sites in muscle fibers. Molecular and Cellular Neuroscience 6(1), 8–89.
MULLER, J. S., MILDNER, G., MULLER-FELBER, W., SCHARA, U., KRAMPFL, K., PETERSEN, B., PETROVA, S., STUCKA, R., MORTIER, W., BUFLER, J., KURLEMANN, G., HUEBNER, A., MERLINI, L., LOCHMULLER, H. & ABICHT, A. (2003) Rapsyn N88K is a frequent cause of congenital myasthenic syndromes in European patients. Neurology 60, 180–1810.
MUSIL, L. S., CARR, C., COHEN, J. B. & MERLIE, J. P. (1988) Acetylcholine receptor-associated 43K protein contains covalently bound myristate. Journal of Cell Biology 107(3), 111–1121.
NAMBA, T. & SCHELLER, R. H. (1996) Inhibition of agrinmediated acetylcholine receptor clustering by utrophin C-terminal peptides. Genes Cells 1(8), 75–764.
NAWROTZKI, R., LOH, N. Y., RUEGG, M. A., DAVIES, K. E. & BLAKE, D. J. (1998) Characterisation of alphadystrobrevin in muscle. Journal of Cell Science 111 (Pt 17), 259–2605.
NEELY, J. D., AMIRY-MOGHADDAM, M., OTTERSEN, O. P., FROEHNER, S. C., AGRE, P. & ADAMS, M. E. (2001) Syntrophin-dependent expression and localization of Aquaporin-4 water channel protein. Proceedings of the National Academy of Sciences USA 98(24), 1410– 14113.
NEWEY, S. E., GRAMOLINI, A. O., WU, J., HOLZFEIND, P., JASMIN, B. J., DAVIES, K. E. & BLAKE, D. J. (2001) A novel mechanism for modulating synaptic gene expression: Differential localization of alphadystrobrevin transcripts in skeletal muscle. Molecular and Cellular Neuroscience 17(1), 12–140.
NOAKES, P. G., PHILLIPS, W. D., HANLEY, T. A., SANES, J. R. & MERLIE, J. P. (1993) 43K protein and acetylcholine receptors colocalize during the initial stages of neuromuscular synapse formation in vivo. Developmental Biology 155(1), 27–280.
OAK, S. A., RUSSO, K., PETRUCCI, T. C. & JARRETT, H. W. (2001) Mouse alpha1-syntrophin binding to Grb2: Further evidence of a role for syntrophin in cell signaling. Biochemistry 40(37), 1127–11278.
OHNO, K., ENGEL, A. G., SHEN, X. M., SELCEN, D., BRENGMAN, J., HARPER C. M., TSUJINO, A. & MILONE, M. (2002) Rapsyn mutations in humans cause endplate acetylcholine-receptor deficiency and myasthenic syndrome. American Journal of Human Genetics 70, 87–885.
OHNO, K., SADEH, M., BLATT, I., BRENGMAN, J. M. & ENGEL, A. G. (2003) E-box mutations in the RAPSN promoter region in eight cases with congenital myasthenic syndrome. Human Molecular Genetics. 12, 73– 748.
ONO, F., HIGASHIJIMA, S., SHCHERBATKO, A., FETCHO, J. R. & BREHM, P. (2001) Paralytic zebrafish lacking acetylcholine receptors fail to localize rapsyn clusters to the synapse. Journal of Neuroscience 21, 543–5448.
OZAWA, E., YOSHIDA, M., SUZUKI, A., MIZUNO, Y., HAGIWARA, Y. & NOGUCHI, S. (1995) Dystrophinassociated proteins in muscular dystrophy.HumanMolecular Genetics 4 Spec No, 171–1716.
PENG, H. B. & FROEHNER, S. C. (1985) Association of the postsynaptic 43K protein with newly formed acetylcholine receptor clusters in cultured muscle cells. Journal of Cell Biology 100(5), 169–1705.
PENG, H. B., XIE, H., ROSSI, S. G. & ROTUNDO, R. L. (1999) Acetylcholinesterase clustering at the neuromuscular junction involves perlecan and dystroglycan. Journal of Cell Biology 145(4), 91–921.
PETERS, M. F., ADAMS, M. E. & FROEHNER, S. C. (1997) Differential association of syntrophin pairs with the dystrophin complex. Journal of Cell Biology 138(1), 8–93.
PETERS, M. F., KRAMARCY, N. R., SEALOCK, R. & FROEHNER, S. C. (1994) beta 2-Syntrophin: Localization at the neuromuscular junction in skeletal muscle. Neuroreport 5(13), 157–1580.
PETERS, M. F., SADOULET-PUCCIO, H. M., GRADY, M. R., KRAMARCY, N. R., KUNKEL, L. M., SANES, J. R., SEALOCK, R. & FROEHNER, S. C. (1998) Differential membrane localization and intermolecular associations of alpha-dystrobrevin isoforms in skeletal muscle. Journal of Cell Biology 142(5), 126–1278.
PHILLIPS, W. D., KOPTA, C., BLOUNT, P., GARDNER, P. D., STEINBACH, J. H. & MERLIE, J. P. (1991a) ACh receptor-rich membrane domains organized in fibroblasts by recombinant 43-kildalton protein. Science 251(4993), 56–570.
PHILLIPS, W. D., MAIMONE, M. M. & MERLIE, J. P. (1991b) Mutagenesis of the 43-kD postsynaptic protein defines domains involved in plasma membrane targeting and AChR clustering. Journal of Cell Biology 115(6), 171–1723.
PHILLIPS, W. D., NOAKES, P. G., ROBERDS, S. L., CAMPBELL, K. P. & MERLIE, J. P. (1993) Clustering and immobilization of acetylcholine receptors by the 43-kDprotein, a possible role for dystrophin-related protein. Journal of Cell Biology 123(3), 72–740.
PHILLIPS, W. D., VLADETA, D., HAN, H. & NOAKES, P. G. (1997) Rapsyn and Agrin slow the metabolic degradation of the acetylcholine receptor. Molecular and Cellular Neuroscience 10(1/2), 1–26.
PILUSO, G., MIRABELLA, M., RICCI, E., BELSITO, A., ABBONDANZA, C., SERVIDEI, S., PUCA, A. A., TONALI, P., PUCA, G. A. & NIGRO, V. (2000) Gamma1-and gamma2-syntrophins, two novel dystrophin-binding proteins localized in neuronal cells. Journal of Biological Chemistry 275(21), 1585–15860.
PONTING, C. C. & PHILLIPS, C. (1996) Rapsyn's knobs and holes: Eight tetratrico peptide repeats. Biochemical Journal 314(Pt 3), 105–1054.
PORTER, S. & FROEHNER, S. C. (1983) Characterization and localization of the Mr = 43,000 proteins associated with acetylcholine receptor-rich membranes. Journal of Biological Chemistry 258(16), 1003–10040.
PORTER, S. & FROEHNER, S. C. (1985) Interaction of the 43K protein with components of Torpedo postsynaptic membranes. Biochemistry 24(2), 42–432.
QU, Z., APEL, E. D., DOHERTY, C. A., HOFFMAN, P. W., MERLIE, J. P. & HUGANIR, R. L. (1996) The synapse-associated protein rapsyn regulates tyrosine phosphorylation of proteins colocalized at nicotinic acetylcholine receptor clusters. Molecular and Cellular Neuroscience 8(2/3), 17–184.
RAMARAO, M. K., BIANCHETTA, M. J., LANKEN, J. & COHEN, J. B. (2001) Role of rapsyn tetratricopeptide repeat and coiled-coil domains in self-association and nicotinic acetylcholine receptor clustering. Journal of Biological Chemistry 276(10), 747–7483.
RAMARAO, M. K. & COHEN, J. B. (1998) Mechanism of nicotinic acetylcholine receptor cluster formation by rapsyn. Proceedings of the National Academy of Sciences USA 95(7), 400–4012.
RICHARD, P., GAUDON, K., ANDREUX, F., YASAKI, E., PRIOLEAU, C., BAUCHE, S., BAROIS, A., IOOS, C., MAYER, M., ROUTON, M. C., MOKHTARI, M., LEROY, J. P., FOURNIER, E., HAINQUE, B., KOENIG, J., FARDEAU, M., EYMARD B. & HANTAI, D. (2003) Possible founder effect of rapsyn N88K mutation and identification of novel rapsyn mutations in congenital myasthenic syndromes. Journal of Medical Genetics 40, e81.
SADOULET-PUCCIO, H. M., KHURANA, T. S., COHEN, J. B. & KUNKEL, L. M. (1996) Cloning and characterization of the human homologue of a dystrophin related phosphoprotein found at the Torpedo electric organ post-synaptic membrane. Human Molecular Genetics 5(4), 48–496.
SANES, J. R., SCHACHNER, M. & COVAULT, J. (1986) Expression of several adhesive macromolecules (NCAM, L1, J1, NILE, uvomorulin, laminin, fibronectin, and a heparan sulfate proteoglycan) in embryonic, adult, and denervated adult skeletal muscle. Journal of Cell Biology 102(2), 42–431.
SCHAEFFER, L., DE KERCHOVE D'EXAERDE, A. & CHANGEUX, J. P. (2001) Targeting transcription to the neuromuscular synapse. Neuron 31(1), 1–22.
SCHULTZ, J., HOFFMULLER, U., KRAUSE, G., ASHURST, J., MACIAS, M. J., SCHMIEDER, P., SCHNEIDER-MERGENER, J. & OSCHKINAT, H. (1998) Specific interactions between the syntrophin PDZ domain and voltage-gated sodium channels. Nature Structural Biology 5(1), 1–24.
SCOTLAND, P. B., COLLEDGE, M., MELNIKOVA, I., DAI, Z. & FROEHNER, S. C. (1993) Clustering of the acetylcholine receptor by the 43-kD protein: Involvement of the zinc finger domain. Journal of Cell Biology 123(3), 71–728.
SEALOCK, R. & FROEHNER, S. C. (1994) Dystrophinassociated proteins and synapse formation: Is alphadystroglycan the agrin receptor? Cell 77(5), 61–619.
SEALOCK, R., WRAY, B. E. & FROEHNER, S. C. (1984) Ultrastructural localization of the Mr 43,000 protein and the acetylcholine receptor in Torpedo postsynaptic membranes using monoclonal antibodies. Journal of Cell Biology 98(6), 223–2244.
SMITH, C. L., MITTAUD, P., PRESCOTT, E. D., FUHRER, C. & BURDEN, S. J. (2001) Src, Fyn, and Yes are not required for neuromuscular synapse formation but are necessary for stabilization of agrin-induced clusters of acetylcholine receptors. Journal of Neuroscience 21(9), 315–3160.
SOBEL, A., HEIDMANN, T. & CHANGEUX, J. P. (1977) Purification of a protein binding quinacrine and histrionicotoxin from membrane fragments rich in cholinergic receptors in Torpedo marmorata. C. R. Acad. Sci. Hebd. Seances Acad. Sci. D. 285(14), 125–1258.
SUGIYAMA, J., BOWEN, D. C. & HALL, Z. W. (1994) Dystroglycan binds nerve and muscle agrin. Neuron 13(1), 10–115.
SUGIYAMA, J. E., GLASS, D. J., YANCOPOULOS, G. D. & HALL, Z. W. (1997) Laminin-induced acetylcholine receptor clustering: An alternative pathway. Journal of Cell Biology 139(1), 18–191.
TINSLEY, J. M., BLAKE, D. J., ROCHE, A., FAIRBROTHER, U., RISS, J., BYTH, B. C., KNIGHT, A. E., KENDRICK-JONES, J., SUTHERS, G. K., LOVE, D. R., et al. (1992) Primary structure of dystrophin-related protein. Nature 360(6404), 59–593.
VAILLEND, C. & BILLARD, J. M. (2002) Facilitated CA1 hippocampal synaptic plasticity in dystrophin-deficient mice: Role for GABAA receptors? Hippocampus 12(6), 71–717.
VAILLEND, C., BILLARD, J. M., CLAUDEPIERRE, T., RENDON, A., DUTAR, P. & UNGERER, A. (1998) Spatial discrimination learning and CA1 hippocampal synaptic plasticity in mdx and mdx3cv mice lacking dystrophin gene products. Neuroscience 86(1), 5–66.
WANG, Z. Z., MATHIAS, A., GAUTAM, M. & HALL, Z. W. (1999) Metabolic stabilization of muscle nicotinic acetylcholine receptor by rapsyn. Journal of Neuroscience 19(6), 199–2007.
WILLMANN, R. & C. FUHRER. (2002) Neuromuscular synaptogenesis: Clustering of acetylcholine receptgors revisited. Cellular and Molecular Life Sciences 59, 129–1316.
YOSHIHARA, C. M. & HALL, Z. W. (1993) Increased expression of the 43-kD protein disrupts acetylcholine receptor clustering in myotubes. Journal of Cell Biology 122(1), 16–179.
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Banks, G.B., Fuhrer, C., Adams, M.E. et al. The postsynaptic submembrane machinery at the neuromuscular junction: Requirement for rapsyn and the utrophin/dystrophin-associated complex. J Neurocytol 32, 709–726 (2003). https://doi.org/10.1023/B:NEUR.0000020619.24681.2b
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DOI: https://doi.org/10.1023/B:NEUR.0000020619.24681.2b