Regulation of the Nicotinic Acetylcholine Receptor by Serine and Tyrosine Protein Kinases

  • Richard L. Huganir
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 287)


Neurotransmitter receptors play a central role in the process of signal transduction across synapses between neurons. Neurotransmitters released from the presynaptic neuron diffuse across the synaptic cleft and bind to neurotransmitter receptors in the membrane of the postsynaptic neuron. The neurotransmitter receptors then transduce this signal across the postsynaptic membrane either by directly activating ion channels or by regulating the level of intracellular second messengers in the postsynaptic neuron. Because of the essential role of neurotransmitter receptors in synaptic transmission, the short and long term modulation of neurotransmitter receptor function could be an extremely effective mechanism for the regulation of synaptic plasticity. What are the molecular mechanisms that may be involved in the modulation of neurotransmitter receptor function? Studies on the regulation of cellular metabolism over the past four decades have shown that protein phosphorylation is the primary mechanisms in the regulation of almost all cellular processes (Edelman et al, 1987, Nairn et al, 1985, Hunter et al, 1985).


Tyrosine Phosphorylation Acetylcholine Receptor Protein Phosphorylation Nicotinic Receptor Nicotinic Acetylcholine Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adamo S, Zani BM, Nerri C., Senni MI, Molinare M, and Eusebi F. (1985). Acetylcholine stimulates phosphatidylinositol turnover at nicotinic receptors of cultured myotubes. FEBS Lett. 190: 161–164.PubMedCrossRefGoogle Scholar
  2. Albuquerque EX, Deshpande SS, Aracava Y, Alkondon M, Daly JW (1986). A possible involvement of cyclic AMP in the expression of desensitization of the nicotinic acetylcholine receptor: a study with forskolin and its analogs. FEBS Lett 199:113–120.PubMedCrossRefGoogle Scholar
  3. Changeux J-P, Devillers-Thiery A, Chemouilli P (1984). Acetylcholine receptor: an allosteric protein. Science 225:1333–1345.CrossRefGoogle Scholar
  4. Claudio T, Ballivet M, Patrick J, Heinemann S (1983). Nucleotide and deduced amino acid sequences of Torpedo californica acetylcholine receptor γ subunit. Proc Natl Acad Sci USA 80:1111–1115.PubMedCrossRefGoogle Scholar
  5. Cohen P (1989). The structure and regulation of protein phosphatases, in “Annual Review of Biochemistry,” Richardson CC, Abelson JN et al, eds., Annual Reviews Inc., Palo Alto, CA.Google Scholar
  6. Devillers-Thiery A, Giraudat J, Benaboulet M, Changeux J-P (1983). Complete mRNA coding sequence of the acetylcholine-binding α-subunit of Torpedo marmorata acetylcholine receptor: a model for the transmembrane organization of the polypeptide chain. Proc Natl Acad Sci USA 80:2067–2071.PubMedCrossRefGoogle Scholar
  7. Edelman AM, Blumenthal DK, Krebs EG (1987). Protein serine/threonine kinases. Annu Rev Biochem 56:567–613.PubMedCrossRefGoogle Scholar
  8. Eusebi F, Molinaro M, Zani BM (1985). Agents that activate protein kinase C reduce acetylcholine sensitivity in cultured myotubes. J Cell Biol 100:1339–1342.PubMedCrossRefGoogle Scholar
  9. Finer-Moore J, Stroud RM (1984). Amphipathic analysis and possible formation of the ion channel in an acetylcholine receptor. Proc Natl Acad Sci USA 81:155–159.PubMedCrossRefGoogle Scholar
  10. Fontaine B, Klarsfeld A, Hokfelt T, Changuex 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 71:59–65.PubMedCrossRefGoogle Scholar
  11. Giraudat J, Dennis M, Heidmann T, Chang J-Y, Changeux J-P (1986). Structure of the high-affinity binding site for noncompetitive blockers of the acetylcholine receptors: serine-262 of the δ is labeled by [3H] chlorpromazine. Proc Natl Acad Sci USA 83:2719–2723.PubMedCrossRefGoogle Scholar
  12. Heilbronn H, Eriksson R, Salmansson R (1985). Regulation of the nicotinic acetylcholine receptor by phosphorylation. In Changeux, Hucho, Maelicke, and Neumann, (eds): “Molecular Basis of Nerve Activity,” Berlin: Walter de Gruyter, pp 237–250.Google Scholar
  13. Hemmings HC, Nairn AC, McGuinness TL, Huganir RL, Greengard P (1989). Role of protein phosphorylation in neuronal signal transduction. FASEB 3:1583–1592.Google Scholar
  14. Hopfield JF, Tank DW, Greengard P, Huganir RL. (1988). Functional modulation of the nicotinic acetylcholine receptor by tyrosine phosphorylation. Nature 336:677–680.PubMedCrossRefGoogle Scholar
  15. Hucho F, Oberthur W, Lottspeich, F (1986). The ion channel of the nicotinic acetylcholine receptor is formed by the homologous helices M II of the receptor subunits. FEBS Lett 205:137–142.PubMedCrossRefGoogle Scholar
  16. Huganir RL, Albert KA, Greengard P (1983). Phosphorylation of the nicotinic acetylcholine receptor by Ca2+/phospholipid-dependent protein kinase, and comparison with its phosphorylation by cAMP-dependent protein kinase. Soc Neurosci Abstr 9:578.Google Scholar
  17. Huganir RL, Delcour AH, Greengard P, Hess GP (1986). Phosphorylation of the nicotinic acetylcholine receptor regulates its rate of desensitization. Nature 321:774–776.PubMedCrossRefGoogle Scholar
  18. Huganir RL, Greengard P (1983). cAMP-dependent protein kinase phosphorylates the nicotinic acetylcholine receptor. Proc Natl Acad Sci USA 80:1130–1134.PubMedCrossRefGoogle Scholar
  19. Huganir RL, Greengard P (1987). Regulation of receptor function by protein phosphorylation. TIPS 8:472–477.Google Scholar
  20. Huganir RL, Miles K, Greengard P (1984). Phosphorylation of the nicotinic acetylcholine receptor by an endogenous tyrosine-specific protein kinase. Proc Natl Acad Sci USA 81:6963–6972.CrossRefGoogle Scholar
  21. Huganir RL, Racker E (1982). Properties of proteoliposimes reconstituted with acetylcholine receptor from Torpedo californica. J Biol Chem 257:9372–9378.PubMedGoogle Scholar
  22. Hunter T, Cooper JA (1985). Protein-tyrosine kinases. Annu Rev Biochem 54:897–930.PubMedCrossRefGoogle Scholar
  23. Imoto K, Busch C, Sakmann B, Mishina M, Konno T, Nakai J, Bujo H, Mori Y, Fukuda K, Numa S. (1988). Rings of negatively charged amino acids determine the acetylcholine receptor channel conductance. Nature 335:645–648.PubMedCrossRefGoogle Scholar
  24. Kao PN, Dwork AJ, Kaldany RRJ, Silver ML, Wideman J, Stein S, Karlin A (1984). Identification of the α subunit Half-cystine specifically labeled by an affinity reagent for the acetylcholine receptor binding site. J Biol Chem 259:11662–11665.PubMedGoogle Scholar
  25. Kobayashi H. Hashimoto K, Sakuma J, Takami K, Tohyama M, Izumi F, Yoshida H (1987). Calcitonin gene-related peptide stimulates adenylate cyclase activity in rat striatal muscle. Experientia 43:314–316.PubMedCrossRefGoogle Scholar
  26. Laufer R, Changeux J-P (1989). Calcitonin gene-related peptide and cyclic AMP stimulate phosphoinositide turnover in skeletal muscle cells: interaction between two second messenger systems. J Biol Chem 264: 2683–2689.PubMedGoogle Scholar
  27. Laufer R, Changeux J-P (1987). Calcitonin gene-related peptide elevates cyclic AMP levels in chick skeletal muscle: possible neurotrophic role for a coexisting neuronal messenger. EMBO J 6:901–906.PubMedGoogle Scholar
  28. Leonard RJ, Labarca CG, Charnet P, Davidson N., Lester HA (1988). Evidence that the M2 Membrane-spanning region lines the ion channel pore of the nicotinic receptor. Science 242:1578–1581.PubMedCrossRefGoogle Scholar
  29. Matteoli M, Haimann C., Torri-Tarelli F, Polak JM Ceccarelli B, DeCamilli P (1988). Differential effect of α-latrotoxin on exocytosis from small synaptic vesicles and from large dense-core vesicles containing calcitonin gene-related peptide at the frog neuromuscular junction. Proc Natl Acad Sci USA 85:7366–7370.PubMedCrossRefGoogle Scholar
  30. McHugh EM, McGee, Jr R (1986). Direct anesthetic-like effects of forskolin on the nicotinic acetylcholine receptors of PC12 cells. J Biol Chem 261:3103–3106.PubMedGoogle Scholar
  31. Middleton P, Jaramillo F, Scheutze SM (1986). Forskolin increases the rate of acetylcholine receptor desensitization at rat soleus endplates. Proc Natl Acad Sci USA 83:4967–4971.PubMedCrossRefGoogle Scholar
  32. Middleton P, Rubin LL, Schuetze SM (1988). Modulation of acetylcholine receptor desensitization in rat myotubes. J Neurosci 8:3405–3412.PubMedGoogle Scholar
  33. Miles K, Anthony DT, Rubin LL, Greengard P, Huganir RL (1987). Regulation of nicotinic acetylcholine receptor phosphorylation in rat myotubes by forskolin and cAMP. Proc Natl Acad Sci USA 84:6591–6595.PubMedCrossRefGoogle Scholar
  34. Miles K, Greengard P, Huganir RL (1989). Calcitonin gene-related peptide regulates phosphorylation of the nicotinic acetylcholine receptor in rat myotubes. Neuron 2: 1517–1524.PubMedCrossRefGoogle Scholar
  35. Miles K, Huganir RL (1988). Regulation of Nicotinic Acetylcholine Receptors by Protein Phosphorylation. Molecular Neurobiology 2:91– 124.PubMedCrossRefGoogle Scholar
  36. Miles K, Greengard P, Huganir RL (1990). Manuscript in preparation.Google Scholar
  37. Mulle C, Benoit P, Pinset C, Roa M, Changuex J-P (1988). Calcitonin gene-related peptide enhances the rate of desensitization of the nicotinic acetylcholine receptor in cultured mouse muscle cell. Proc Natl Acad Sci USA 85:5728–5732.PubMedCrossRefGoogle Scholar
  38. Nairn AC, Hemmings HC, Greengard P (1985). Protein kinases in the brain. Annu Rev Biochem 54:931–976.PubMedCrossRefGoogle Scholar
  39. New HV, and Mudge AW (1986). Calcitonin gene-related peptide regulates muscle acetylcholine receptor synthesis. Nature 323:809–811.PubMedCrossRefGoogle Scholar
  40. Noda M, Takahashi H, Tanabe T, Toyosato M, Furutani Y, Hirose T, Asai M, Inayama S, Miyata T, Numa S (1982). Primary structure of α-subunit precursor of Torpedo californica acetylcholine receptor deduced from cDNA sequence. Nature 299:793–797.PubMedCrossRefGoogle Scholar
  41. Noda M, Takahashi H, Tanabe T, Toyosato M, Kikyotani S, Furutani Y, Hirose T, Takashima H, Inayama S, Miyata T, Numa S (1983). Structural homology of Torpedo californica acetylcholine receptor subunits. Nature 302:528–532.PubMedCrossRefGoogle Scholar
  42. Noda M, Takahashi H, Tanabe T, Toyosato M, Kikyotani S, Hirose T, Asai M, Takashima H, Inayama S, Miyata T, Numa S (1983). Primary structures of ß and δ subunit precursors of Torpedo californica acetylcholine receptor deduced from cDNA sequences. Nature 301:251–255.PubMedCrossRefGoogle Scholar
  43. Qu Z, Moritz E, Huganir RL (1990). Regulation of tyrosine phosphorylation of the nicotinic acetylcholine receptor at the rat neuromuscular junction. Neuron, in press.Google Scholar
  44. Raftery MA, Hunkapiller MW, Strader CD, Hood LE (1980). Acetylcholine receptor: complex of homologous subunits. Science 208:1454–1457.PubMedCrossRefGoogle Scholar
  45. Reynolds JA, Karlin A (1978). Molecular weight in detergent solution of acetylcholine receptor from Torpedo californica. Biochemistry 17:2035–2038.PubMedCrossRefGoogle Scholar
  46. Ross A, Rapuano M, and Prives J. (1988). Induction of phosphorylation and cell surface redistribution of acetylcholine receptors by phorbol ester and carbamylcholine in cultured chick muscle cells. J Cell Biol 107:1139–1145PubMedCrossRefGoogle Scholar
  47. Ross A, Rapuano M, Schmidt J, Prives J (1987). Phosphorylation and assembly of nicotinic acetylcholine receptor subunits in cultured chick muscle cells. J Biol Chem 262:14640–14647.PubMedGoogle Scholar
  48. Safran A, Eisenberg RS, Neumann D, Fuchs S (1987). Phosphorylation of the acetylcholine receptor by protein kinase C and identification of the phosphorylation site within the receptor δ subunit. J Biol Chem 262:10506–10510.PubMedGoogle Scholar
  49. Smilowitz H, Hadjian RA, Dwyer J, Feinstein MB (1981). Regulation of acetylcholine receptor phosphorylation by calcium and calmodulin. Proc Natl Acad Sci USA 78:4708–4712.PubMedCrossRefGoogle Scholar
  50. Smith MM, Merlie JP, Lawrence, Jr JC, (1987). Regulation of phosphorylation of nicotinic acetylcholine receptors in mouse BC3H1 myocytes. Proc Natl Acad Sci USA 84:6601–6605.PubMedCrossRefGoogle Scholar
  51. Smith MM, Merlie JP, Lawrence Jr. JC (1989). Ca+2-dependent and cAMP-dependent control of nicotinic acetylcholine receptor phophorylation in muscle cells. J Biol Chem 264: 12813–12819.PubMedGoogle Scholar
  52. Takami K, Hashimito K, Uchida S, Tohyama M, Yashida H. (1986). Effect of calcitonin gene-related peptide on the cyclic AMP level of isolated mouse diaphragm. Jap J Pharmacol 42:345–350.PubMedCrossRefGoogle Scholar
  53. Tank DE, Huganir RL. Greenard P, Webb WW (1983). Patch-recorded single-channel currents of the purified and reconstituted Torpedo acetylcholine receptor. Proc Natl Acad Sci USA 80:5129–5133.PubMedCrossRefGoogle Scholar
  54. Wagoner PK, Pallotta BS (1988). Modulation of acetylcholine receptor desensitization by forskolin is independent of cAMP. Science 240:1655–1657.PubMedCrossRefGoogle Scholar
  55. Yee GH, Huganir RL (1987). Determination of the sites of cAMP-dependent phosphorylation on the nicotinic acetylcholine receptor. J Biol Chem 262: 16748–16753.PubMedGoogle Scholar
  56. Zavoico GB, Comerci C, Subers E, Egon JJ, Huang CK, Feinstein MB, Smilowitz H (1984). cAMP, not Ca2+/calmodulin, regulates the phosphorylation of acetylcholine receptor in Torpedo californica electroplax. Biochim Biophys Acta 770:225–229.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Richard L. Huganir
    • 1
  1. 1.Howard Hughes Medical Institute, Department of NeuroscienceThe Johns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations