Journal of Neurocytology

, Volume 32, Issue 5–8, pp 727–741 | Cite as

Postsynaptic signaling of new players at the neuromuscular junction



The neuromuscular junction (NMJ) represents the most well studied synapse and is widely regarded as structurally and functionally less complicated than neuronal synapses in the brain. Recent studies, however, have identified the localization and function of new signaling molecules at the NMJ. Surprisingly, many synaptic proteins previously identified in the brain are indeed also concentrated on the postsynaptic muscle side of the NMJ. These include the serine/threonine kinase Cdk5, the neurotrophin receptor TrkB, Eph receptors and ephrins, NMDA receptors and nitric oxide synthase, various PDZ-domain scaffold proteins, and β-amyloid precursor protein. These observations indicate that the molecular composition of NMJ is much more intricate than we originally thought. The potential significance of these new signaling molecules at the NMJ will be discussed.


Nitric Oxide NMDA NMDA Receptor Precursor Protein Neuromuscular Junction 


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  1. AHERN, G. P., KLYACHKO, V. A. & JACKSON, M. B. (2002) cGMP and S-nitrosylation: Two routes for modulation of neuronal excitability by NO. Trends Neurosci. 25, 51–517.PubMedGoogle Scholar
  2. AKAABOUNE, M., MA, J., FESTOFF, B. W., GREENBERG, B. D. & HANTAI, D. (1994) Neurotrophic regulation of mouse muscle beta-amyloid protein precursor and alpha 1-antichymotrypsin as revealed by axotomy. J. Neurobiol. 25, 50–514.PubMedGoogle Scholar
  3. AKAABOUNE, M., ALLINQUANT, B., FARZA, H., ROY, K., MAGOUL, R., FISZMAN, M., FESTOFF, B. W. & HANTAI, D. (2000) Developmental regulation of amyloid precursor protein at the neuromuscular junction in mouse skeletal muscle. Mol. Cell. Neurosci. 15, 35–367.PubMedGoogle Scholar
  4. ALTIOK, N., BESSEREAU, J. L. & CHANGEUX, J. P. (1995) ErbB3 and ErbB2/neu mediate the effect of heregulin on acetylcholine receptor gene expression in muscle: Differential expression at the endplate. EMBO J. 14, 425–4266.PubMedGoogle Scholar
  5. ALTIOK, N., ALTIOK, S. & CHANGEUX, J. P. (1997) Heregulin-stimulated acetylcholine receptor gene expression in muscle: Requirement for MAP kinase and evidence for a parallel inhibitory pathway independent of electrical activity. EMBO J. 16, 71–725.PubMedGoogle Scholar
  6. ASKANAS, V., ENGEL, W. K. & ALVAREZ, R. B. (1992) Strong immunoreactivity of beta-amyloid precursor 736 LAI and IP protein, including the beta-amyloid protein sequence, at human neuromuscular junctions. Neurosci. Lett. 143, 9–100.PubMedGoogle Scholar
  7. BELLUARDO, N., WESTERBLAD, H., MUDO, G., CASABONA, A., BRUTON, J., CANIGLIA, G., PASTORIS, O., GRASSI, F. & IBANEZ, C. F. (2001) Neuromuscular junction disassembly and muscle fatigue in mice lacking neurotrophin-4. Mol. Cell. Neurosci. 18, 5–67.PubMedGoogle Scholar
  8. BERGER, U. V., CARTER, R. E. & COYLE, J. T. (1995) The immunocytochemical localization of N-acetylaspartyl glutamate, its hydrolysing enzyme NAALADase, and the NMDAR-1 receptor at a vertebrate neuromuscular junction. Neuroscience 64, 84–850.PubMedGoogle Scholar
  9. BIBB, J. A., SNYDER, G. L., NISHI, A., YAN, Z., MEIJER, L., FIENBERG, A. A., TSAI, L. H., KWON, Y. T., GIRAULT, J. A., CZERNIK, A. J., HUGANIR, R. L., HEMMINGS, H. C. JR., NAIRN, A. C. & GREENGARD, P. (1999) Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature 402, 66–671.PubMedGoogle Scholar
  10. 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, 75–767.PubMedGoogle Scholar
  11. BUONANNO, A. & FISCHBACH, G. D. (2001) Neuregulin and ErbB receptor signaling pathways in the nervous system. Curr. Opin. Neurobiol. 11, 28–296.PubMedGoogle Scholar
  12. 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.PubMedGoogle Scholar
  13. BURDEN, S. J. (1998) The formation of neuromuscular synapses. Genes Dev. 12, 13–148.PubMedGoogle Scholar
  14. 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, 66–674.PubMedGoogle Scholar
  15. CHENG, K., LI, Z., FU, W. Y., WANG, J. H., FU, A. K. & IP, N. Y. (2002) Pctaire1 interacts with p35 and is a novel substrate for Cdk5/p35. J. Biol. Chem. 277, 3198–31993.PubMedGoogle Scholar
  16. CHOI, R. C., MAN, M. L., LING, K. K., IP, N. Y., SIMON, J., BARNARD, E. A. & TSIM, K. W. (2001) Expression of the P2Y1 nucleotide receptor in chick muscle: Its functional role in the regulation of acetylcholinesterase and acetylcholine receptor. J. Neurosci. 21, 922–9234.PubMedGoogle Scholar
  17. COHEN, I., RIMER, M., LOMO, T. & MCMAHAN, U. J. (1997) Agrin-induced postsynaptic-like apparatus in skeletal muscle fibers in vivo. Mol. Cell. Neurosci. 9, 23–253.PubMedGoogle Scholar
  18. CONNOLLY, J. A. (1984) Role of the cytoskeleton in the formation, stabilization and removal of acetylcholine receptor clusters in cultured muscle cells. J. Cell Biol. 99, 14–154.PubMedGoogle Scholar
  19. DAI, Z., LUO, X., XIE, H. & PENG, H. B. (2000) The actindriven movement and formation of acetylcholine receptor clusters. J. Cell Biol. 150, 132–1334.PubMedGoogle Scholar
  20. DALVA, M. B., TAKASU, M. A., LIN, M. Z., SHAMAH, S. M., HU, L., GALE, N. W. & GREENBERG, M. E. (2000) EphB receptors interact with NMDA receptors and regulate excitatory synapse formation. Cell 103, 94– 956.PubMedGoogle Scholar
  21. 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, 50–512.PubMedGoogle Scholar
  22. 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. (1997) Postsynaptic abnormalities at the neuromuscular junctions of utrophin-deficient mice. J. Cell Biol. 136, 88–894.PubMedGoogle Scholar
  23. DE KERCHOVE D'EXAERDE, A., CARTAUD, J., RAVELCHAPUIS, A., SEROZ, T., PASTEAU, F., ANGUS, L. M., JASMIN, B. J., CHANGEUX, J. P. & SCHAEFFER, L. (2002) Expression of mutant Ets protein at the neuromuscular synapse causes alterations in morphology and gene expression. EMBO Rep. 3, 107–1081.PubMedGoogle Scholar
  24. DHAVAN, R. & TSAI, L. H. (2001) A decade of CDK5. Nat. Rev. Mol. Cell Biol. 2, 74–759.PubMedGoogle Scholar
  25. DHAVAN, R., GREER, P. L., MORABITO, M. A., ORLANDO, L. R. & TSAI, L. H. (2002) The cyclindependent kinase 5 activators p35 and p39 interact with the alpha-subunit of Ca2+/calmodulin-dependent protein kinase II and alpha-actinin-1 in a calcium-dependent manner. J. Neurosci. 22, 787–7891.PubMedGoogle Scholar
  26. DONG, H., O'BRIEN, R. J., FUNG, E. T., LANAHAN, A. A., WORLEY, P. F. & HUGANIR, R. L. (1997) GRIP: AsynapticPDZdomain-containing protein that interacts with AMPA receptors. Nature 386, 27–284.PubMedGoogle Scholar
  27. DUCLERT, A. & CHANGEUX, J. P. (1995) Acetylcholine receptor gene expression at the developing neuromuscular junction. Physiol. Rev. 75, 33–368.PubMedGoogle Scholar
  28. ELOWE, S., HOLLAND, S. J., KULKARNI, S. & PAWSON, T. (2001) Downregulation of the Rasmitogen-activated protein kinase pathway by the EphB2 receptor tyrosine kinase is required for ephrin-induced neurite retraction. Mol. Cell. Biol. 21, 742–7441.PubMedGoogle Scholar
  29. FALLS, D. L., ROSEN, K. M., CORFAS, G., LANE, W. S. & FISCHBACH, G. D. (1993) ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family. Cell 72, 80–815.PubMedGoogle Scholar
  30. FERNS, M., DEINER, M. & HALL, Z. (1996) Agrin-induced acetylcholine receptor clustering in mammalian muscle requires tyrosine phosphorylation. J. Cell Biol. 132, 93–944.PubMedGoogle Scholar
  31. FISCHBACH, G. D. & ROSEN, K. M. (1997) ARIA: A neuromuscular junction neuregulin. Annu. Rev. Neurosci. 20, 42–458.PubMedGoogle Scholar
  32. FONTAINE, B., KLARSFELD, A., HOKFELT, T. & CHANGEUX, J. P. (1986) Calcitonin gene-related peptide, a peptide present in spinal cord motoneurons, increases the number of acetylcholine receptors in primary cultures of chick embryo myotubes. Neurosci. Lett. 71, 5–65.PubMedGoogle Scholar
  33. FU, A. K., SMITH, F. D., ZHOU, H., CHU, A. H., TSIM, K. W., PENG, B. H. & IP, N. Y. (1999a) Xenopus New molecular players at the neuromuscular junction 737 muscle-specific kinase: Molecular cloning and prominent expression in neural tissues during early embryonic development. Eur. J. Neurosci. 11, 37–382.PubMedGoogle Scholar
  34. FU, A. K., CHEUNG, W. M., IP, F. C. & IP, N. Y. (1999b) Identification of genes induced by neuregulin in cultured myotubes. Mol. Cell. Neurosci. 14, 24–253.PubMedGoogle Scholar
  35. FU, A. K., CHEUNG, J., SMITH, F. D., IP, F. C. & IP, N. Y. (2001a) Overexpression of muscle specific kinase increases the transcription and aggregation of acetylcholine receptors in Xenopus embryos. Mol. Brain Res. 96, 2–29.PubMedGoogle Scholar
  36. FU, A. K., FU, W. Y., CHEUNG, J., TSIM, K. W., IP, F. C., WANG, J. H. & IP, N. Y. (2001b) Cdk5 is involved in neuregulin-induced AChR expression at the neuromuscular junction. Nat. Neurosci. 4, 37–381.PubMedGoogle Scholar
  37. FU, W. Y., FU, A. K., LOK, K. C., IP, F. C. & IP, N. Y. (2002) Induction of Cdk5 activity in rat skeletal muscle after nerve injury. Neuroreport 13, 24–247.PubMedGoogle Scholar
  38. FUNAKOSHI, H., FRISEN, J., BARBANY, G., TIMMUSK, T., ZACHRISSON, O., VERGE, V. M. & PERSSON, H. (1993) Differential expression of mRNAs for neurotrophins and their receptors after axotomy of the sciatic nerve. J. Cell Biol. 123, 45–65.PubMedGoogle Scholar
  39. GAO, W.-Q., SHINSKY, N., ARMANINI, M. P., MORAN, P., ZHENG, J. L., MENDOZA-RAMIREZ, J. L., PHILLIPS, H. S., WINSLOW, J. W. & CARAS, I. W. (1998) Regulation of hippocampal synaptic plasticity by the tyrosine kinase receptor, Rek7/ EphA5, and its ligand, AL-1/Ephrin-A5. Mol. Cell. Neurosci. 11, 24– 259.PubMedGoogle Scholar
  40. GARCIA, R. A., VASUDEVAN, K. & BUONANNO, A. (2000) The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses. Proc. Natl. Acad. Sci. 97, 359–3601.PubMedGoogle Scholar
  41. 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, 52–535.PubMedGoogle Scholar
  42. GERLAI, R., SHINSKY, N., SHIH, A., WILLIAMS, P., WINER, J., ARMANINI, M., CAIRNS, B., WINSLOW, J., GAO, W.-Q. & PHILLIPS, H. S. (1999) Regulation of learning by EphA receptors: A protein targeting study. J. Neurosci. 19, 953–9549.PubMedGoogle Scholar
  43. GLASS, D. J., BOWEN, D. C., STITT, T. N., RADZIEJEWSKI, C., BRUNO, J., RYAN, T. E., GIES, D. R., SHAH, S., MATTSSON, K., BURDEN, S. J., DISTEFANO, P. S., VALENZUELA, D. M., DECHIARA, T. M. & YANCOPOULOS, G. D. (1996) Agrin acts via a MuSK receptor complex. Cell 85, 51–523.PubMedGoogle Scholar
  44. GLASS, D. J., APEL, E. D., SHAH, S., BOWEN, D. C., DECHIARA, T. M., STITT, T. N., SANES, J. R. & YANCOPOULOS, G. D. (1997) Kinase domain of the muscle-specific receptor tyrosine kinase (MuSK) is sufficient for phosphorylation but not clustering of acetylcholine receptors: Required role for the MuSK ectodomain? Proc. Natl. Acad. Sci. 94, 884–8853.PubMedGoogle Scholar
  45. GODFREY, E. W., NITKIN, R. M., WALLACE, B. G., RUBIN, L. L. & MCMAHAN, U. J. (1984) Components of Torpedo electric organ and muscle that cause aggregation of acetylcholine receptors on cultured muscle cells. J. Cell Biol. 99, 61–627.PubMedGoogle Scholar
  46. GONZALEZ, M., RUGGIERO, F. P., CHANG, Q., SHI, Y.-J., RICH, M. M., KRANER, S. & BALICEGORDON, R. J. (1999) Disruption of TrkB-mediated signaling induces disassembly of postsynaptic receptor clusters at neuromuscular junctions. Neuron 24, 56– 583.PubMedGoogle Scholar
  47. GRADY, R. M., MERLIE, J. P. & SANES, J. R. (1997) Subtle neuromuscular defects in utrophin-deficient mice. J. Cell Biol. 136, 87–882.PubMedGoogle Scholar
  48. GRAESER, R., GANNON, J., POON, R. Y., DUBOIS, T., AITKEN, A. & HUNT T. (2002) Regulation of the CDKrelated protein kinase PCTAIRE-1 and its possible role in neurite outgrowth in Neuro-2A cells. J. Cell Sci. 115, 347–3490.PubMedGoogle Scholar
  49. GROZDANOVIC, Z. & GOSSRAU, R. (1998) Colocalization of nitric oxide synthase I (NOS I) andNMDA receptor subunit 1 (NMDAR-1) at the neuromuscular junction in rat and mouse skeletal muscle. Cell Tissue Res. 291, 5–63.PubMedGoogle Scholar
  50. GRUNWALD, I. C., KORTE, M., WOLFER, D., WILKINSON, G. A., UNSICKER, K., LIPP, H. P., BONHOEFFER, T. & KLEIN, R. (2001) Kinaseindependent requirement of EphB2 receptors in hippocampal synaptic plasticity. Neuron 32, 102– 1040.PubMedGoogle Scholar
  51. GUAN, B., HARTMANN, B., KHO, Y. H., GORCZYCA, M. & BUDNIK, V. (1996) The Drosophila tumor suppressor gene, dlg, is involved in structural plasticity at a glutamatergic synapse. Curr. Biol. 6, 69–706.PubMedGoogle Scholar
  52. HARRIS, D. A., FALLS, D. L., DILL-DEVOR, R. M. & FISCHBACH G. D. (1988) Acetylcholine receptorinducing factor from chicken brain increases the level of mRNA encoding the receptor alpha subunit. Proc. Natl. Acad. Sci. 85, 198–1987.PubMedGoogle Scholar
  53. HENDERSON, J. T., GEORGIOU, J., JIA, Z., ROBERTSON, J., ELOWE, S., RODER, J. C. & PAWSON, T. (2001) The receptor tyrosine kinase EphB2 regulates NMDA-dependent synaptic function. Neuron 32, 104–1056.PubMedGoogle Scholar
  54. HOCH, W., CAMPANELLI, J. T. & SCHELLER, R. H. (1994) Agrin-induced clustering of acetylcholine receptors: A cytoskeletal link. J. Cell Biol. 126, –4.PubMedGoogle Scholar
  55. HOCK, B., BOHME, B., KARN, T., YAMAMOTO, T., KAIBUCHI, K., HOLTRICH, U., HOLLAND, S., PAWSON, T., RUBSAMEN-WAIGMANN, H. & STREBHARDT, K. (1998) PDZ-domain-mediated interaction of the Eph-related receptor tyrosine kinase EphB3 and the ras-binding protein AF6 depends on the kinase activity of the receptor. Proc. Natl. Acad. Sci. 95, 977–9784.PubMedGoogle Scholar
  56. HUANG, C., NI, Y., WANG, T., GAO, Y., HAUDENSCHILD, C. C. & ZHAN, X. (1997) Downregulation of the filamentous actin cross-linking activity of cortactin by Src-mediated tyrosine phosphorylation. J. Biol. Chem. 272, 1391–13915.PubMedGoogle Scholar
  57. HUANG, Y. Z., WON, S., ALI, D. W., WANG, Q., TANOWITZ, M., DU, Q. S., PELKEY, K. A., YANG, D. J., XIONG, W. C., SALTER, M. W. & MEI, L. (2000) Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses. Neuron 26, 44–455.PubMedGoogle Scholar
  58. HUANG, Y. Z., WANG, Q., XIONG, W. C. & MEI, L. (2001) Erbin is a protein concentrated at postsynaptic 738 LAI and IP membranes that interacts with PSD-95. J. Biol. Chem. 276, 1931–19326.PubMedGoogle Scholar
  59. HUMBERT, S., LANIER, L. M. & TSAI, L. H. (2000) Synaptic localization of p39, a neuronal activator of cdk5. Neuroreport 11, 221–2216.PubMedGoogle Scholar
  60. IP, N. Y. & YANCOPOULOS, G. D. (1996) The neurotrophins and CNTF: Two families of collaborative neurotrophic factors. Annu. Rev. Neurosci. 19, 49–515.PubMedGoogle Scholar
  61. IP, F. C. F., GLASS, D. G., GIES, D. R., CHEUNG, J., LAI. K. O., FU, A. K., YANCOPOULOS, G. D. & IP, N. Y. (2000) Cloning and characterization of muscle-specific kinase in chicken. Mol. Cell. Neurosci. 16, 66–673.PubMedGoogle Scholar
  62. IWASAKI, Y., GAY, B., WADA, K. & KOIZUMI, S. (1998) Association of the Src family tyrosine kinase Fyn with TrkB. J. Neurochem. 71, 10–111.PubMedGoogle Scholar
  63. 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, 15–161.PubMedGoogle Scholar
  64. JONES, G., MEIER, T., LICHTSTEINER, M., WITZEMANN, V., SAKMANN, B. & BRENNER, H. R. (1997) Induction by agrin of ectopic and functional postsynaptic-like membrane in innervated muscle. Proc. Natl. Acad. Sci. USA 94, 265–2659.PubMedGoogle Scholar
  65. JONES, M. A. & WERLE, M. J. (2000) Nitric oxide is a downstream mediator of agrin-induced acetylcholine receptor aggregation. Mol. Cell. Neurosci. 16, 64–660.PubMedGoogle Scholar
  66. KALIMAN, P., CANICIO, J., TESTAR, X., PALACIN, M. & ZORZANO, A. (1999) Insulin-like growth factor-II, phosphatidylinositol 3-kinase, nuclear factor-kappaB and inducible nitric-oxide synthase define a common myogenic signaling pathway. J. Biol. Chem. 274, 1743–17444.PubMedGoogle Scholar
  67. KILPATRICK, T. J., BROWN, A., LAI, C., GASSMANN, M., GOULDING, M. & LEMKE, G. (1996) Expression of the Tyro4/Mek4/Cek4 gene specifically marks a subset of embryonic motor neurons and their muscle targets. Mol. Cell. Neurosci. 7, 6–74.PubMedGoogle Scholar
  68. KIM, E., NIETHAMMER, M., ROTHSCHILD, A., JAN, Y. N. & SHENG, M. (1995) Clustering of Shaker-type K+ channels by interaction with a family of membraneassociated guanylate kinases. Nature 378, 8–88.PubMedGoogle Scholar
  69. KOBZIK, L., STRINGER, B., BALLIGAND, J. L., REID, M. B. & STAMLER, J. S. (1995) Endothelial type nitric oxide synthase in skeletal muscle fibers: Mitochondrial relationships. Biochem. Biophys. Res. Commun. 211, 37–381.PubMedGoogle Scholar
  70. KORNAU, H. C., SCHENKER, L. T., KENNEDY, M. B. & SEEBURG, P. H. (1995) Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science 269, 173–1740.PubMedGoogle Scholar
  71. KORTE, M., CARROLL, P., WOLF, E., BREM, G., THOENEN, H. & BONHOEFFER, T. (1995) Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc. Natl. Acad. Sci. 92, 885–8860.PubMedGoogle Scholar
  72. KULLANDER, K. & KLEIN, R. (2002) Mechanisms and functions of Eph and ephrin signalling. Nat. Rev. Mol. Cell Biol. 3, 47–486.PubMedGoogle Scholar
  73. LAI, K. O., IP, F. C. & IP, N. Y. (1999) Identification and characterization of splice variants of ephrin-A3 and ephrin-A5. FEBS Lett. 458, 26–269.PubMedGoogle Scholar
  74. LAI, K. O., IP, F. C. F., CHEUNG, J., FU, A. K. Y. & IP, N. Y. (2001) Expression of Eph receptors in skeletal muscle and their localization at the neuromuscular junction. Mol. Cell. Neurosci. 17, 103–1047.PubMedGoogle Scholar
  75. LAI, K. O. & IP, N. Y. (2003) Central synapse and neuromuscular junction: Same players, different roles. Trends Genet. 19, 39–402.PubMedGoogle Scholar
  76. LAZARO, J. B., KITZMANN, M., POUL, M. A., VANDROMME, M., LAMB, N. J. & FERNANDEZ, A. (1997) Cyclin dependent kinase 5, cdk5, is a positive regulator of myogenesis in mouse C2 cells. J. Cell Sci. 110, 125–1260.PubMedGoogle Scholar
  77. LI, B. S., SUN, M. K., ZHANG, L., TAKAHASHI, S., MA, W., VINADE, L., KULKARNI, A. B., BRADY, R. O. & PANT, H. C. (2001) Regulation of NMDA receptors by cyclin-dependent kinase-5. Proc. Natl. Acad. Sci. 98, 1274–12747.PubMedGoogle Scholar
  78. LIN, J. W., WYSZYNSKI, M., MADHAVAN, R., SEALOCK, R., KIM, J. U. & SHENG, M. (1998) Yotiao, a novel protein of neuromuscular junction and brain that interacts with specific splice variants of NMDA receptor subunit NR1. J. Neurosci. 18, 201–2027.PubMedGoogle Scholar
  79. LIN, W., SANCHEZ, H. B., DEERINCK, T., MORRIS, J. K., ELLISMAN, M. & LEE, K. F. (2000) Aberrant development of motor axons and neuromuscular synapses in erbB2-deficient mice. Proc. Natl. Acad. Sci. 97, 129–1304.PubMedGoogle Scholar
  80. 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, 105–1064.PubMedGoogle Scholar
  81. LIU, F., MA, X. H., ULE, J., BIBB, J. A., NISHI, A., DEMAGGIO, A. J., YAN, Z., NAIRN, A. C. & GREENGARD, P. (2001) Regulation of cyclin-dependent kinase 5 and casein kinase 1 by metabotropic glutamate receptors. Proc. Natl. Acad. Sci. 98, 1106–11068.PubMedGoogle Scholar
  82. LOHOF, A. M., IP, N. Y. & POO, M. M. (1993) Potentiation of developing neuromuscular synapses by the neurotrophins NT-3 and BDNF. Nature 363, 35–353.PubMedGoogle Scholar
  83. LU, B. & CHOW, A. (1999) Neurotrophins and hippocampal synaptic transmission and plasticity. J. Neurosci. Res. 58, 7–87.PubMedGoogle Scholar
  84. LU, J. T., SON, Y. J., LEE, J., JETTON, T. L., SHIOTA, M., MOSCOSO, L., NISWENDER, K. D., LOEWY, A. D., MAGNUSON, M. A., SANES, J. R. & EMESON, R. B. (1999) Mice lacking alpha-calcitonin gene-related peptide exhibit normal cardiovascular regulation and neuromuscular development. Mol. Cell. Neurosci. 14, 9–120.PubMedGoogle Scholar
  85. LÑCK, G., HOCH, W., HOPF, C. & BLOTTNER, D. (2000) Nitric oxide synthase (NOS-1) coclustered with agrininduced AChR-specializations on cultured skeletal myotubes. Mol. Cell. Neurosci. 16, 26–281.PubMedGoogle Scholar
  86. LUO, Z. G., WANG, Q., ZHOU, J. Z., WANG, J., LUO, Z., LIU, M., HE, X., WYNSHAW-BORIS, A., XIONG, W. C., LU, B. & MEI, L. (2002) Regulation of AChR clustering by Dishevelled interacting with MuSK and PAK1. Neuron 35, 48–505.PubMedGoogle Scholar
  87. MARANGI, P. A., WIELAND, S. T. & FUHRER, C. (2002) Laminin-1 redistributes postsynaptic proteins and requires rapsyn, tyrosine phosphorylation, and Src and Fyn New molecular players at the neuromuscular junction 739 to stably cluster acetylcholine receptors. J. Cell Biol. 157, 88–895.PubMedGoogle Scholar
  88. MARTINOU, J. C., FALLS, D. L., FISCHBACH, G. D. & MERLIE, J. P. (1991) Acetylcholine receptor-inducing activity stimulates expression of the ?-sub-unit gene of the muscle acetylcholine receptor. Proc. Natl. Acad. Sci. USA. 88, 766–7673.PubMedGoogle Scholar
  89. MEIER, T., PEREZ, G. M. & WALLACE, B. G. (1995) Immobilization of nicotinic acetylcholine receptors in mouse C2 myotubes by agrin-induced protein tyrosine phosphorylation. J. Cell Biol. 131, 44–451.PubMedGoogle Scholar
  90. MEIER, T., HAUSER, D. M., CHIQUET, M., LANDMANN, L., RUEGG, M. A. & BRENNER, H. R. (1997) Neural agrin induces ectopic postsynaptic specializations in innervated muscle fibers. J. Neurosci. 17, 653–6544.PubMedGoogle Scholar
  91. MEIER, T., MASCIULLI, F., MOORE, C., SCHOUMACHER, F., EPPENBERGER, U., DENZER, A. J., JONES, G. & BRENNER, H. R. (1998) Agrin can mediate acetylcholine receptor gene expression in muscle by aggregation of muscle-derived neuregulins. J. Cell Biol. 141, 71–726.PubMedGoogle Scholar
  92. MEIER, T. & WALLACE, B. G. (1998) Formation of the neuromuscular junction: Molecules and mechanisms. BioEssays 20, 81–829.PubMedGoogle Scholar
  93. MEIMA, L., KLJAVIN, I. J., MORAN, P., SHIH, A., WINSLOW, J. W. & CARAS, I. W. (1997) AL-1-induced growth cone collapse of rat cortical neurons is correlated with REK7 expression and rearrangement of the actin cytoskeleton. Eur. J. Neurosci. 9, 17–188.PubMedGoogle Scholar
  94. MIAO, H., WEI, B. R., PEEHL, D. M., LI, Q., ALEXANDROU, T., SCHELLING, J. R., RHIM, J. S., SEDOR, J. R., BURNETT, E. & WANG, B. (2001) Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway. Nat. Cell Biol. 3, 52–530.PubMedGoogle Scholar
  95. MIGAUD, M., CHARLESWORTH, P., DEMPSTER, M., WEBSTER, L. C., WATABE, A. M., MAKHINSON, M., HE, Y., RAMSAY, M. F., MORRIS, R. G., MORRISON, J. H., O'DELL, T. J. & GRANT, S. G. (1998) Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 396, 41–415.PubMedGoogle Scholar
  96. 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. J. Biol. Chem. 276, 1450–14513.PubMedGoogle Scholar
  97. 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. J. Neurosci. 21, 380–3818.PubMedGoogle Scholar
  98. MORIMOTO, T., OHSAWA, I., TAKAMURA, C., ISHIGURO, M., NAKAMURA, Y. & KOHSAKA, S. (1998) Novel domain-specific actions of amyloid precursor protein on developing synapses. J. Neurosci. 18, 938–9393.PubMedGoogle Scholar
  99. MORRIS, J. K., LIN, W., HAUSER, C., MARCHUK, Y., GETMAN, D. & LEE, K. F. (1999) Rescue of the cardiac defect in ErbB2 mutant mice reveals essential roles of ErbB2 in peripheral nervous system development. Neuron 23, 27–283.PubMedGoogle Scholar
  100. MOSCOSO, L. M., CHU, G. C., GAUTAM, M., NOAKES, P. G., MERLIE, J. P. & SANES, J. R. (1995) Synapse-associated expression of an acetylcholine receptor-inducing protein, ARIA/heregulin, and its putative receptors, ErbB2 and ErbB3, in developing mammalian muscle. Dev. Biol. 172, 15– 169.PubMedGoogle Scholar
  101. MUCKE, L., MASLIAH, E., JOHNSON, W. B., RUPPE, M. D., ALFORD, M., ROCKENSTEIN, E. M., FORSSPETTER, S., PIETROPAOLO, M., MALLORY, M. & ABRAHAM, C. R. (1994) Synaptotrophic effects of human amyloid beta protein precursors in the cortex of transgenic mice. Brain Res. 666, 15–167.PubMedGoogle Scholar
  102. NAMBA, T. & SCHELLER, R. H. (1996) Inhibition of agrinmediated acetylcholine receptor clustering by utrophin C-terminal peptides. Genes. Cells. 1, 75–64.PubMedGoogle Scholar
  103. NEW, H. V. & MUDGE, A. W. (1986) Calcitonin generelated peptide regulates muscle acetylcholine receptor synthesis. Nature 323, 80–811.PubMedGoogle Scholar
  104. NIETHAMMER, M., KIM, E. & SHENG, M. (1996) Interaction between the C terminus of NMDA receptor subunits and multiple members of the PSD-95 family of membrane-associated guanylate kinases. J. Neurosci. 16, 215–2163.PubMedGoogle Scholar
  105. NITKIN, R. M., SMITH, M. A., MAGILL, C., FALLON, J. R., YAO, Y. M., WALLACE, B. G. & MCMAHAN, U. J. (1987) Identification of agrin, a synaptic organizing protein from Torpedo electric organ. J. Cell Biol. 105, 247–2478.PubMedGoogle Scholar
  106. OLIVER, L., GOUREAU, O., COURTOIS, Y. & VIGNY, M. (1996) Accumulation of NO synthase (type-I) at the neuromuscular junctions in adult mice. Neuroreport 7, 92–926.PubMedGoogle Scholar
  107. OPPENHEIM, R. W., YIN, Q. W., PREVETTE, D. & YAN, Q. (1992) Brain-derived neurotrophic factor rescues developing avian motoneurons from cell death. Nature 360, 75–757.PubMedGoogle Scholar
  108. PATTERSON, S. L., ABEL, T., DEUEL, T. A., MARTIN, K. C., ROSE, J. C. & KANDEL, E. R. (1996) Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron 16, 113–1145.PubMedGoogle Scholar
  109. RAFAEL, J. A., HUTCHINSON, T. L., LUMENG, C. N., MARFATIA, S. M., CHISHTI, A. H. & CHAMBERLAIN, J. S. (1998) Localization of Dlg at the mammalian neuromuscular junction. Neuroreport 9, 212–2125.PubMedGoogle Scholar
  110. RIMER, M., COHEN, I., LOMO, T., BURDEN, S. J. & MCMAHAN, U. J. (1998) Neuregulins and erbB receptors at neuromuscular junctions and at agrin-induced postsynaptic-like apparatus in skeletal muscle. Mol. Cell. Neurosci. 12, –15.PubMedGoogle Scholar
  111. RUEGG, M. A., TSIM, K. W., HORTON, S. E., KROGER, S., ESCHER, G., GENSCH, E. M. & MCMAHAN, U. J. (1992) The agrin gene codes for a family of basal lamina proteins that differ in function and distribution. Neuron 8, 69–699.PubMedGoogle Scholar
  112. RUPP, F., PAYAN, D. G., MAGILL-SOLC, C., COWAN, D. M. & SCHELLER, R. H. (1991) Structure and expression of a rat agrin. Neuron 6, 81–823.PubMedGoogle Scholar
  113. SALMON, A. M., DAMAJ, I., SEKINE, S., PICCIOTTO, M. R., MARUBIO, L. & CHANGEUX, J. P. (1999) Modulation of morphine analgesia in alphaCGRP mutant mice. Neuroreport 10, 84–854.PubMedGoogle Scholar
  114. SANDROCK, A. W., JR., DRYER, S. E., ROSEN, K. M., GOZANI, S. N., KRAMER, R., THEILL, L. E. & FISCHBACH, G. D. (1997) Maintenance of acetylcholine receptor number by neuregulins at the neuromuscular junction in vivo. Science 276, 59–603.PubMedGoogle Scholar
  115. SANES, J. R. & LICHTMAN, J. W. (1999) Development of the vertebrate neuromuscular junction. Annu. Rev. Neurosci. 22, 38–442.PubMedGoogle Scholar
  116. SANES, J. R. & LICHTMAN, J. W. (2001) Induction, assembly, maturation and maintenance of a postsynaptic apparatus. Nat. Rev. Neurosci. 2, 79–805.PubMedGoogle Scholar
  117. SCHAEFFER, L., DE KERCHOVE D'EXAERDE, A. & CHANGEUX, J. P. (2001) Targeting transcription to the neuromuscular synapse. Neuron 31, 1–22.PubMedGoogle Scholar
  118. SCHUBERT, W., PRIOR, R., WEIDEMANN, A., DIRCKSEN, H., MULTHAUP, G., MASTERS, C. L. & BEYREUTHER, K. (1991) Localization of Alzheimer beta A4 amyloid precursor protein at central and peripheral synaptic sites. Brain Res. 563, 18–194.PubMedGoogle Scholar
  119. 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. J. Cell Biol. 98, 223–2244.PubMedGoogle Scholar
  120. SENDTNER, M., HOLTMANN, B., KOLBECK, R., THOENEN, H. & BARDE, Y. A. (1992) Brain-derived neurotrophic factor prevents the death of motoneurons in newborn rats after nerve section. Nature 360, 75–759.PubMedGoogle Scholar
  121. SHENG, M. & SALA, C. (2001) PDZ domains and the organization of supramolecular complexes. Annu. Rev. Neurosci. 24, –29.PubMedGoogle Scholar
  122. SI, J., LUO, Z. & MEI, L. (1996) Induction of acetylcholine receptor gene expression by ARIA requires activation of mitogen-activated protein kinase. J. Biol. Chem. 271, 1975–19759.PubMedGoogle Scholar
  123. SI, J., WANG, Q. & MEI, L. (1999) Essential roles of c-JUN and c-JUN N-terminal kinase (JNK) in neuregulinincreased expression of the acetylcholine receptor epsilon-subunit. J. Neurosci. 19, 849–8508.PubMedGoogle Scholar
  124. SLATER, C. R. (1982) Neural influence on the postnatal changes in acetylcholine receptor distribution at nervemuscle junctions in the mouse. Dev. Biol. 94, 2–30.PubMedGoogle Scholar
  125. 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. J. Neurosci. 21, 315–3160.PubMedGoogle Scholar
  126. SOANS, C., HOLASH, J. A., PAVLOVA, Y. & PASQUALE, E. B. (1996) Developmental expression and distinctive tyrosine phosphorylation of the Eph-related receptor tyrosine kinase Cek9. J. Cell Biol. 135, 78–795.PubMedGoogle Scholar
  127. STEIN, E., HUYNH-DO, U., LANE, A. A., CERRETTI, D. P. & DANIEL, T. O. (1998) Nck recruitment to Eph receptor, EphB1/ELK, couples ligand activation to c-Jun kinase. J. Biol. Chem. 273, 130–1308.PubMedGoogle Scholar
  128. STROCHLIC, L., CARTAUD, A., LABAS, V., HOCH, W., ROSSIER, J. & CARTAUD, J. (2001) MAGI-1c: A synaptic MAGUK interacting with MuSK at the vertebrate neuromuscular junction. J. Cell Biol. 153, 112–1132.PubMedGoogle Scholar
  129. TAKASU, M. A., DALVA, M. B., ZIGMOND, R. E. & GREENBERG, M. E. (2002) Modulation of NMDA receptor-dependent calcium influx and gene expression through EphB receptors. Science 295, 49–495.PubMedGoogle Scholar
  130. TANG, D., YEUNG, J., LEE, K. Y., MATSUSHITA, M., MATSUI, H., TOMIZAWA, K., HATASE, O. & WANG, J. H. (1995) An isoform of the neuronal cyclindependent kinase 5 (Cdk5) activator. J. Biol. Chem. 270, 2689–26903.PubMedGoogle Scholar
  131. TANG, H., CHEUNG, W. M., IP, F. C. & IP, N. Y. (2000) Identification and characterization of differentially expressed genes in denervated muscle. Mol. Cell. Neurosci. 16, 12–140.PubMedGoogle Scholar
  132. TANSEY, M. G., CHU, G. C. & MERLIE, J. P. (1996) ARIA/HRG regulates AChR epsilon subunit gene expression at the neuromuscular synapse via activation of phosphatidylinositol 3-kinase and Ras/MAPK pathway. J. Cell Biol. 134, 46–476.PubMedGoogle Scholar
  133. TEJEDOR, F. J., BOKHARI, A., ROGERO, O., GORCZYCA, M., ZHANG, J., KIM, E., SHENG, M. & BUDNIK, V. (1997) Essential role for dlg in synaptic clustering of Shaker K+ channels in vivo. J. Neurosci. 17, 15–159.PubMedGoogle Scholar
  134. THOENEN, H. (1995) Neurotrophins and neuronal plasticity. Science 270, 59–598.PubMedGoogle Scholar
  135. THOMAS, U., KIM, E., KUHLENDAHL, S., KOH, Y. H., GUNDELFINGER, E. D., SHENG, M., GARNER, C. C. & BUDNIK, V. (1997) Synaptic clustering of the cell adhesion molecule fasciclin II by discs-large and its role in the regulation of presynaptic structure. Neuron 19, 78–799.PubMedGoogle Scholar
  136. TINSLEY, J. M., BLAKE, D. J., ZUELLIG, R. A. & DAVIES, K. E. (1994) Increasing complexity of the dystrophin-associated protein complex. Proc. Natl. Acad. Sci. 91, 830–8313.PubMedGoogle Scholar
  137. TOMIZAWA, K., OHTA, J., MATSUSHITA, M., MORIWAKI, A., LI, S. T., TAKEI, K. & MATSUI, H. (2002) Cdk5/p35 regulates neurotransmitter release through phosphorylation and downregulation of P/Q-type voltage-dependent calcium channel activity. J. Neurosci. 22, 259–2597.PubMedGoogle Scholar
  138. TORRES, R., FIRESTEIN, B. L., DONG, H., STAUDINGER, J., OLSON, E. N., HUGANIR, R. L., BREDT, D. S., GALE, N. W. & YANCOPOULOS, G. D. (1998) PDZ proteins bind, cluster, and synaptically colocalize with Eph receptors and their ephrin ligands. Neuron 21, 145–1463.PubMedGoogle Scholar
  139. TSAI, L. H., DELALLE, I., CAVINESS, V. S. JR., CHAE, T. & HARLOW, E. (1994) p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature 371, 41–423.PubMedGoogle Scholar
  140. USDIN, T. B. & FISCHBACH, G. D. (1986) Purification and characterization of a polypeptide from chick brain that promotes the accumulation of acetylcholine receptors in chick myotubes. J. Cell Biol. 103, 49–507.PubMedGoogle Scholar
  141. VALENZUELA, D. M., STITT, T. N., DISTEFANO, P. S., ROJAS, E., MATTSSON, K., COMPTON, D. L., NUNEZ, L., PARK, J. S., STARK, J. L. & GIES, D. R. (1995) Receptor tyrosine kinase specific for the skeletal muscle lineage: Expression in embryonic muscle, at the neuromuscular junction, and after injury. Neuron 15, 57–584.PubMedGoogle Scholar
  142. WAERHAUG, O. & OTTERSEN, O. P. (1993) Demonstration of glutamate-like immunoreactivity at rat neuromuscular junctions by quantitative electron microscopic immunocytochemistry. Anat. Embryol. 188, 50–513.PubMedGoogle Scholar
  143. WALLACE, B. G. (1995) Regulation of the interaction of nicotinic acetylcholine receptors with the cytoskeleton by agrin-activated protein tyrosine kinase. J. Cell Biol. 128, 112–1129.PubMedGoogle Scholar
  144. WANG, X. H. & POO, M. M. (1997) Potentiation of developing synapses by postsynaptic release of neurotrophin-4. Neuron 19, 82–835.PubMedGoogle Scholar
  145. WELLS, D. G., MCKECHNIE, B. A., KELKAR, S. & FALLON, J. R. (1999) Neurotrophins regulate agrininduced postsynaptic differentiation. Proc. Natl. Acad. Sci. 96, 111–1117.PubMedGoogle Scholar
  146. WESTON, C., YEE, B., HOD, E. & PRIVES, J. (2000) Agrininduced acetylcholine receptor clustering is mediated by the small guanosine triphosphatases Rac and Cdc42. J. Cell Biol. 150, 20–212.PubMedGoogle Scholar
  147. WU, K., XU, J. L., SUEN, P. C., LEVINE, E., HUANG, Y. Y., MOUNT, H. T., LIN, S. Y. & BLACK, I. B. (1996) Functional trkB neurotrophin receptors are intrinsic components of the adult brain postsynaptic density. Mol. Brain Res. 43, 28–290.PubMedGoogle Scholar
  148. XU, R. & SALPETER, M. M. (1997) Acetylcholine receptors in innervated muscles of dystrophic mdx mice degrade as after denervation. J. Neurosci. 17, 819–8200.PubMedGoogle Scholar
  149. XU, Z., LAI, K. O., ZHOU, H. M., LIN, S. C. & IP, N. Y. (2003) Ephrin-B1 reverse signaling activatesJNKthrough a novel mechanism that is independent of tyrosine phosphorylation. J. Biol. Chem. 278, 2476–24775.PubMedGoogle Scholar
  150. ZHENG, H., JIANG, M., TRUMBAUER, M. E., SIRINATHSINGHJI, D. J., HOPKINS, R., SMITH, D. W., HEAVENS, R. P., DAWSON, G. R., BOYCE, S., CONNER, M. W., et al. (1995) beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 81, 52–531.PubMedGoogle Scholar
  151. ZHU, X., LAI, C., THOMAS, S. & BURDEN, S. J. (1995) Neuregulin receptors, erbB3 and erbB4, are localized at neuromuscular synapses. EMBO J. 14, 584–5848.PubMedGoogle Scholar
  152. ZITO, K., FETTER, R. D., GOODMAN, C. S. & ISACOFF, E. Y. (1997) Synaptic clustering of Fascilin II and Shaker: Essential targeting sequences and role of Dlg. Neuron 19, 100–1016.PubMedGoogle Scholar

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© Kluwer Academic Publishers 2003

Authors and Affiliations

  1. 1.Department of Biochemistry, Molecular Neuroscience Center and Biotechnology Research InstituteHong Kong University of Science and TechnologyHong KongChina

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