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Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 1999 Feb 28;354(1381):411–416. doi: 10.1098/rstb.1999.0394

Processing of ARIA and release from isolated nerve terminals.

B Han 1, G D Fischbach 1
PMCID: PMC1692493  PMID: 10212491

Abstract

The neuromuscular junction is a specialized synapse in that every action potential in the presynaptic nerve terminal results in an action potential in the postsynaptic membrane, unlike most interneuronal synapses where a single presynaptic input makes only a small contribution to the population postsynaptic response. The postsynaptic membrane at the neuromuscular junction contains a high density of neurotransmitter (acetylcholine) receptors and a high density of voltage-gated Na+ channels. Thus, the large acetylcholine activated current occurs at the same site where the threshold for action potential generation is low. Acetylcholine receptor inducing activity (ARIA), a 42 kD protein, that stimulates synthesis of acetylcholine receptors and voltage-gated Na+ channels in cultured myotubes, probably plays the same roles at developing and mature motor endplates in vivo. ARIA is synthesized as part of a larger, transmembrane, precursor protein called proARIA. Delivery of ARIA from motor neuron cell bodies in the spinal cord to the target endplates involves several steps, including proteolytic cleavage of proARIA. ARIA is also expressed in the central nervous system and it is abundant in the molecular layer of the cerebellum. In this paper we describe our first experiments on the processing and release of ARIA from subcellular fractions containing synaptosomes from the chick cerebellum as a model system.

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Selected References

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  1. Altiok N., Bessereau J. L., Changeux J. P. ErbB3 and ErbB2/neu mediate the effect of heregulin on acetylcholine receptor gene expression in muscle: differential expression at the endplate. EMBO J. 1995 Sep 1;14(17):4258–4266. doi: 10.1002/j.1460-2075.1995.tb00100.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Burgess T. L., Ross S. L., Qian Y. X., Brankow D., Hu S. Biosynthetic processing of neu differentiation factor. Glycosylation trafficking, and regulated cleavage from the cell surface. J Biol Chem. 1995 Aug 11;270(32):19188–19196. doi: 10.1074/jbc.270.32.19188. [DOI] [PubMed] [Google Scholar]
  3. Carraway K. L., 3rd, Weber J. L., Unger M. J., Ledesma J., Yu N., Gassmann M., Lai C. Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases. Nature. 1997 May 29;387(6632):512–516. doi: 10.1038/387512a0. [DOI] [PubMed] [Google Scholar]
  4. Chang H., Riese D. J., 2nd, Gilbert W., Stern D. F., McMahan U. J. Ligands for ErbB-family receptors encoded by a neuregulin-like gene. Nature. 1997 May 29;387(6632):509–512. doi: 10.1038/387509a0. [DOI] [PubMed] [Google Scholar]
  5. Chu G. C., Moscoso L. M., Sliwkowski M. X., Merlie J. P. Regulation of the acetylcholine receptor epsilon subunit gene by recombinant ARIA: an in vitro model for transynaptic gene regulation. Neuron. 1995 Feb;14(2):329–339. doi: 10.1016/0896-6273(95)90289-9. [DOI] [PubMed] [Google Scholar]
  6. Corfas G., Fischbach G. D. The number of Na+ channels in cultured chick muscle is increased by ARIA, an acetylcholine receptor-inducing activity. J Neurosci. 1993 May;13(5):2118–2125. doi: 10.1523/JNEUROSCI.13-05-02118.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ericson J., Thor S., Edlund T., Jessell T. M., Yamada T. Early stages of motor neuron differentiation revealed by expression of homeobox gene Islet-1. Science. 1992 Jun 12;256(5063):1555–1560. doi: 10.1126/science.1350865. [DOI] [PubMed] [Google Scholar]
  8. Falls D. L., Rosen K. M., Corfas G., Lane W. S., Fischbach G. D. ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family. Cell. 1993 Mar 12;72(5):801–815. doi: 10.1016/0092-8674(93)90407-h. [DOI] [PubMed] [Google Scholar]
  9. Fischbach G. D., Rosen K. M. ARIA: a neuromuscular junction neuregulin. Annu Rev Neurosci. 1997;20:429–458. doi: 10.1146/annurev.neuro.20.1.429. [DOI] [PubMed] [Google Scholar]
  10. GRAY E. G., WHITTAKER V. P. The isolation of nerve endings from brain: an electron-microscopic study of cell fragments derived by homogenization and centrifugation. J Anat. 1962 Jan;96:79–88. [PMC free article] [PubMed] [Google Scholar]
  11. Goodearl A. D., Yee A. G., Sandrock A. W., Jr, Corfas G., Fischbach G. D. ARIA is concentrated in the synaptic basal lamina of the developing chick neuromuscular junction. J Cell Biol. 1995 Sep;130(6):1423–1434. doi: 10.1083/jcb.130.6.1423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hall Z. W., Sanes J. R. Synaptic structure and development: the neuromuscular junction. Cell. 1993 Jan;72 (Suppl):99–121. doi: 10.1016/s0092-8674(05)80031-5. [DOI] [PubMed] [Google Scholar]
  13. Holmes W. E., Sliwkowski M. X., Akita R. W., Henzel W. J., Lee J., Park J. W., Yansura D., Abadi N., Raab H., Lewis G. D. Identification of heregulin, a specific activator of p185erbB2. Science. 1992 May 22;256(5060):1205–1210. doi: 10.1126/science.256.5060.1205. [DOI] [PubMed] [Google Scholar]
  14. Kramer R., Bucay N., Kane D. J., Martin L. E., Tarpley J. E., Theill L. E. Neuregulins with an Ig-like domain are essential for mouse myocardial and neuronal development. Proc Natl Acad Sci U S A. 1996 May 14;93(10):4833–4838. doi: 10.1073/pnas.93.10.4833. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Loeb J. A., Fischbach G. D. ARIA can be released from extracellular matrix through cleavage of a heparin-binding domain. J Cell Biol. 1995 Jul;130(1):127–135. doi: 10.1083/jcb.130.1.127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Loeb J. A., Susanto E. T., Fischbach G. D. The neuregulin precursor proARIA is processed to ARIA after expression on the cell surface by a protein kinase C-enhanced mechanism. Mol Cell Neurosci. 1998 May;11(1-2):77–91. doi: 10.1006/mcne.1998.0676. [DOI] [PubMed] [Google Scholar]
  17. Marchionni M. A., Goodearl A. D., Chen M. S., Bermingham-McDonogh O., Kirk C., Hendricks M., Danehy F., Misumi D., Sudhalter J., Kobayashi K. Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature. 1993 Mar 25;362(6418):312–318. doi: 10.1038/362312a0. [DOI] [PubMed] [Google Scholar]
  18. Martinou J. C., Falls D. L., Fischbach G. D., Merlie J. P. Acetylcholine receptor-inducing activity stimulates expression of the epsilon-subunit gene of the muscle acetylcholine receptor. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7669–7673. doi: 10.1073/pnas.88.17.7669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Meier T., Perez G. M., Wallace B. G. Immobilization of nicotinic acetylcholine receptors in mouse C2 myotubes by agrin-induced protein tyrosine phosphorylation. J Cell Biol. 1995 Oct;131(2):441–451. doi: 10.1083/jcb.131.2.441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Meyer D., Birchmeier C. Multiple essential functions of neuregulin in development. Nature. 1995 Nov 23;378(6555):386–390. doi: 10.1038/378386a0. [DOI] [PubMed] [Google Scholar]
  21. Miledi R., Zelená J. Sensitivity to acetylcholine in rat slow muscle. Nature. 1966 May 21;210(5038):855–856. doi: 10.1038/210855a0. [DOI] [PubMed] [Google Scholar]
  22. Missias A. C., Chu G. C., Klocke B. J., Sanes J. R., Merlie J. P. Maturation of the acetylcholine receptor in skeletal muscle: regulation of the AChR gamma-to-epsilon switch. Dev Biol. 1996 Oct 10;179(1):223–238. doi: 10.1006/dbio.1996.0253. [DOI] [PubMed] [Google Scholar]
  23. Missias A. C., Mudd J., Cunningham J. M., Steinbach J. H., Merlie J. P., Sanes J. R. Deficient development and maintenance of postsynaptic specializations in mutant mice lacking an 'adult' acetylcholine receptor subunit. Development. 1997 Dec;124(24):5075–5086. doi: 10.1242/dev.124.24.5075. [DOI] [PubMed] [Google Scholar]
  24. Moscoso L. M., Chu G. C., Gautam M., Noakes P. G., Merlie J. P., Sanes J. R. Synapse-associated expression of an acetylcholine receptor-inducing protein, ARIA/heregulin, and its putative receptors, ErbB2 and ErbB3, in developing mammalian muscle. Dev Biol. 1995 Nov;172(1):158–169. doi: 10.1006/dbio.1995.0012. [DOI] [PubMed] [Google Scholar]
  25. Nitkin R. M., Smith M. A., Magill C., Fallon J. R., Yao Y. M., Wallace B. G., McMahan U. J. Identification of agrin, a synaptic organizing protein from Torpedo electric organ. J Cell Biol. 1987 Dec;105(6 Pt 1):2471–2478. doi: 10.1083/jcb.105.6.2471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ozaki M., Sasner M., Yano R., Lu H. S., Buonanno A. Neuregulin-beta induces expression of an NMDA-receptor subunit. Nature. 1997 Dec 18;390(6661):691–694. doi: 10.1038/37795. [DOI] [PubMed] [Google Scholar]
  27. Peles E., Bacus S. S., Koski R. A., Lu H. S., Wen D., Ogden S. G., Levy R. B., Yarden Y. Isolation of the neu/HER-2 stimulatory ligand: a 44 kd glycoprotein that induces differentiation of mammary tumor cells. Cell. 1992 Apr 3;69(1):205–216. doi: 10.1016/0092-8674(92)90131-u. [DOI] [PubMed] [Google Scholar]
  28. Rio C., Rieff H. I., Qi P., Khurana T. S., Corfas G. Neuregulin and erbB receptors play a critical role in neuronal migration. Neuron. 1997 Jul;19(1):39–50. doi: 10.1016/s0896-6273(00)80346-3. [DOI] [PubMed] [Google Scholar]
  29. Role L. W., Matossian V. R., O'Brien R. J., Fischbach G. D. On the mechanism of acetylcholine receptor accumulation at newly formed synapses on chick myotubes. J Neurosci. 1985 Aug;5(8):2197–2204. doi: 10.1523/JNEUROSCI.05-08-02197.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sandrock A. W., Jr, Dryer S. E., Rosen K. M., Gozani S. N., Kramer R., Theill L. E., Fischbach G. D. Maintenance of acetylcholine receptor number by neuregulins at the neuromuscular junction in vivo. Science. 1997 Apr 25;276(5312):599–603. doi: 10.1126/science.276.5312.599. [DOI] [PubMed] [Google Scholar]
  31. Sandrock A. W., Jr, Goodearl A. D., Yin Q. W., Chang D., Fischbach G. D. ARIA is concentrated in nerve terminals at neuromuscular junctions and at other synapses. J Neurosci. 1995 Sep;15(9):6124–6136. doi: 10.1523/JNEUROSCI.15-09-06124.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Tandon A., Bannykh S., Kowalchyk J. A., Banerjee A., Martin T. F., Balch W. E. Differential regulation of exocytosis by calcium and CAPS in semi-intact synaptosomes. Neuron. 1998 Jul;21(1):147–154. doi: 10.1016/s0896-6273(00)80522-x. [DOI] [PubMed] [Google Scholar]
  33. Tsuchida T., Ensini M., Morton S. B., Baldassare M., Edlund T., Jessell T. M., Pfaff S. L. Topographic organization of embryonic motor neurons defined by expression of LIM homeobox genes. Cell. 1994 Dec 16;79(6):957–970. doi: 10.1016/0092-8674(94)90027-2. [DOI] [PubMed] [Google Scholar]
  34. Usdin T. B., Fischbach G. D. Purification and characterization of a polypeptide from chick brain that promotes the accumulation of acetylcholine receptors in chick myotubes. J Cell Biol. 1986 Aug;103(2):493–507. doi: 10.1083/jcb.103.2.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Wen D., Peles E., Cupples R., Suggs S. V., Bacus S. S., Luo Y., Trail G., Hu S., Silbiger S. M., Levy R. B. Neu differentiation factor: a transmembrane glycoprotein containing an EGF domain and an immunoglobulin homology unit. Cell. 1992 May 1;69(3):559–572. doi: 10.1016/0092-8674(92)90456-m. [DOI] [PubMed] [Google Scholar]
  36. Zhang D., Sliwkowski M. X., Mark M., Frantz G., Akita R., Sun Y., Hillan K., Crowley C., Brush J., Godowski P. J. Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4. Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9562–9567. doi: 10.1073/pnas.94.18.9562. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Zhu X., Lai C., Thomas S., Burden S. J. Neuregulin receptors, erbB3 and erbB4, are localized at neuromuscular synapses. EMBO J. 1995 Dec 1;14(23):5842–5848. doi: 10.1002/j.1460-2075.1995.tb00272.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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