Regulation of cholinergic activity by the vesicular acetylcholine transporter

Biochemical Journal

Volumn 450, Issue 2, 2013, Pages 265-274

  Prado, Vania F ^a,b   Roy, Ashbeel ^a,b   Kolisnyk, Benjamin ^a   Gros, Robert ^a,b   Prado, Marco A M ^a,b  

^a ROBARTS RESEARCH INSTITUTE   (Canada)

^b UNIVERSITY OF WESTERN ONTARIO   (Canada)

Author keywords

Alzheimer's disease; Heart failure; Parkinson's disease; Sepsis; Synaptic vesicle; Vascular dementia

Indexed keywords

ACETYLCHOLINE; VESAMICOL; VESICULAR ACETYLCHOLINE TRANSPORTER;

ACETYLCHOLINE RELEASE; AUTONOMIC NERVOUS SYSTEM; CELL MIGRATION; CHOLINERGIC ACTIVITY; CHOLINERGIC NERVE CELL; NEUROTRANSMITTER RELEASE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; PROTEIN STRUCTURE; REVIEW; SYNAPSE VESICLE;

ACETYLCHOLINE; ANIMALS; HUMANS; MICE; NEURONS; SYNAPTIC TRANSMISSION; SYNAPTIC VESICLES; VESICULAR ACETYLCHOLINE TRANSPORT PROTEINS;

EID: 84874084137     PISSN: 02646021     EISSN: 14708728     Source Type: Journal    
DOI: 10.1042/BJ20121662     Document Type: Review

References (161)

1. El Mestikawy, S., Wallen-Mackenzie, A., Fortin, G. M., Descarries, L. and Trudeau, L. E. (2011) From glutamate co-release to vesicular synergy: vesicular glutamate transporters. Nat. Rev. Neurosci. 12, 204-216
2. Wessler, I. and Kirkpatrick, C. J. (2008) Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans. Br. J. Pharmacol. 154, 1558-1571
3. Wessler, I. K. and Kirkpatrick, C. J. (2012) Activation of muscarinic receptors by non-neuronal acetylcholine. Handb. Exp. Pharmacol. 208, 469-491
4. Prado,M. A., Reis, R. A., Prado, V. F., de Mello, M. C., Gomez, M. V. and deMello, F. G. (2002) Regulation of acetylcholine synthesis and storage. Neurochem. Int. 41, 291-299
5. Rocha-Resende, C., Roy, A., Resende, R., Ladeira, M. S., Lara, A., de Morais Gomes, E. R., Prado, V. F., Gros, R., Guatimosim, C., Prado, M. A. and Guatimosim, S. (2012) Non-neuronal cholinergic machinery present in cardiomyocytes offsets hypertrophic signals. J. Mol. Cell. Cardiol. 53, 206-216
6. Rodriguez-Diaz, R., Dando, R., Jacques-Silva, M. C., Fachado, A., Molina, J., Abdulreda, M. H., Ricordi, C., Roper, S. D., Berggren, P. O. and Caicedo, A. (2011) Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans. Nat. Med. 17, 888-892
7. Ribeiro, F. M., Black, S. A., Prado, V. F., Rylett, R. J., Ferguson, S. S. and Prado, M. A. (2006) The 'ins' and 'outs' of the high-affinity choline transporter CHT1. J. Neurochem. 97, 1-12
8. Parsons, S. M. (2000) Transport mechanisms in acetylcholine and monoamine storage. FASEB J. 14, 2423-2434
9. Vardy, E., Arkin, I. T., Gottschalk, K. E., Kaback, H. R. and Schuldiner, S. (2004) Structural conservation in the major facilitator superfamily as revealed by comparative modeling. Protein Sci. 13, 1832-1840
10. Varoqui, H. and Erickson, J. D. (1996) Active transport of acetylcholine by the human vesicular acetylcholine transporter. J. Biol. Chem. 271, 27229-27232
11. Hori, T. and Takahashi, T. (2012) Kinetics of synaptic vesicle refilling with neurotransmitter glutamate. Neuron 76, 511-517
12. Wess, J. (2012) Novel muscarinic receptor mutant mouse models. Handb. Exp. Pharmacol. 208, 95-117
13. Wess, J., Eglen, R. M. and Gautam, D. (2007) Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development. Nat. Rev. Drug Discovery 6, 721-733
14. Wess, J. (2004) Muscarinic acetylcholine receptor knockout mice: novel phenotypes and clinical implications. Annu. Rev. Pharmacol. Toxicol. 44, 423-450
15. Bymaster, F. P., McKinzie, D. L., Felder, C. C. and Wess, J. (2003) Use of M1-M5 muscarinic receptor knockout mice as novel tools to delineate the physiological roles of the muscarinic cholinergic system. Neurochem. Res. 28, 437-442
16. Changeux, J. P. (2010) Nicotine addiction and nicotinic receptors: lessons from genetically modified mice. Nat. Rev. Neurosci. 11, 389-401
17. Champtiaux, N. and Changeux, J. P. (2004) Knockout and knockin mice to investigate the role of nicotinic receptors in the central nervous system. Prog. Brain Res. 145, 235-251
18. Cordero-Erausquin, M., Marubio, L. M., Klink, R. and Changeux, J. P. (2000) Nicotinic receptor function: new perspectives from knockout mice. Trends Pharmacol. Sci. 21, 211-217
19. Khare, P., Ojeda, A. M., Chandrasekaran, A. and Parsons, S. M. (2010) Possible important pair of acidic residues in vesicular acetylcholine transporter. Biochemistry 49, 3049-3059
20. Nguyen, M. L., Cox, G. D. and Parsons, S. M. (1998) Kinetic parameters for the vesicular acetylcholine transporter: two protons are exchanged for one acetylcholine. Biochemistry 37, 13400-13410
21. Ojeda, A. M., Kolmakova, N. G. and Parsons, S. M. (2004) Acetylcholine binding site in the vesicular acetylcholine transporter. Biochemistry 43, 11163-11174
22. Kim, M. H., Lu, M., Lim, E. J., Chai, Y. G. and Hersh, L. B. (1999) Mutational analysis of aspartate residues in the transmembrane regions and cytoplasmic loops of rat vesicular acetylcholine transporter. J. Biol. Chem. 274, 673-680
23. Bravo, D. T., Kolmakova, N. G. and Parsons, S. M. (2005) Mutational and pH analysis of ionic residues in transmembrane domains of vesicular acetylcholine transporter. Biochemistry 44, 7955-7966
24. Van der Kloot, W. (2003) Loading and recycling of synaptic vesicles in the Torpedo electric organ and the vertebrate neuromuscular junction. Prog. Neurobiol. 71, 269-303
25. Song, H., Ming, G., Fon, E., Bellocchio, E., Edwards, R. H. and Poo, M. (1997) Expression of a putative vesicular acetylcholine transporter facilitates quantal transmitter packaging. Neuron 18, 815-826
26. Prado, V. F., Martins-Silva, C., de Castro, B. M., Lima, R. F., Barros, D. M., Amaral, E., Ramsey, A. J., Sotnikova, T. D., Ramirez, M. R., Kim, H. G. et al. (2006) Mice deficient for the vesicular acetylcholine transporter are myasthenic and have deficits in object and social recognition. Neuron 51, 601-612
27. Lima, R. F., Prado, V. F., Prado, M. A. and Kushmerick, C. (2010) Quantal release of acetylcholine in mice with reduced levels of the vesicular acetylcholine transporter. J. Neurochem. 113, 943-951
28. Prior, C., Marshall, I. G. and Parsons, S. M. (1992) The pharmacology of vesamicol: an inhibitor of the vesicular acetylcholine transporter. Gen. Pharmacol. 23, 1017-1022
29. Tu, Z., Wang, W., Cui, J., Zhang, X., Lu, X., Xu, J. and Parsons, S. M. (2012) Synthesis and evaluation of in vitro bioactivity for vesicular acetylcholine transporter inhibitors containing two carbonyl groups. Bioorg. Med. Chem. 20, 4422-4429
30. Efange, S. M., Khare, A. B., von, H. K., Mach, R. H., Parsons, S. M. and Tu, Z. (2010) Synthesis and in vitro biological evaluation of carbonyl group-containing inhibitors of vesicular acetylcholine transporter. J. Med. Chem. 53, 2825-2835
31. Gras, C., Amilhon, B., Lepicard, E. M., Poirel, O., Vinatier, J., Herbin, M., Dumas, S., Tzavara, E. T., Wade, M. R., Nomikos, G. G. et al. (2008) The vesicular glutamate transporter VGLUT3 synergizes striatal acetylcholine tone. Nat. Neurosci. 11, 292-300
32. Hnasko, T. S. and Edwards, R. H. (2012) Neurotransmitter corelease: mechanism and physiological role. Annu. Rev. Physiol. 74, 225-243
33. Trudeau, L. E. and Gutierrez, R. (2007) On cotransmission and neurotransmitter phenotype plasticity. Mol. Interv. 7, 138-146
34. Mendez, J. A., Bourque, M. J., Dal Bo, G., Bourdeau, M. L., Danik, M., Williams, S., Lacaille, J. C. and Trudeau, L. E. (2008) Developmental and target-dependent regulation of vesicular glutamate transporter expression by dopamine neurons. J. Neurosci. 28, 6309-6318
35. Tritsch, N. X., Ding, J. B. and Sabatini, B. L. (2012) Dopaminergic neurons inhibit striatal output through non-canonical release of GABA. Nature 490, 262-266
36. Bravo, D. T., Kolmakova, N. G. and Parsons, S. M. (2004) Choline is transported by vesicular acetylcholine transporter. J. Neurochem. 91, 766-768
37. Bravo, D. T., Kolmakova, N. G. and Parsons, S. M. (2005) New transport assay demonstrates vesicular acetylcholine transporter has many alternative substrates. Neurochem. Int. 47, 243-247
38. Khare, P., Mulakaluri, A. and Parsons, S. M. (2010) Search for the acetylcholine and vesamicol binding sites in vesicular acetylcholine transporter: the region around the lumenal end of the transport channel. J. Neurochem. 115, 984-993
39. Barbosa, Jr, J., Clarizia, A. D., Gomez, M. V., RomanoSilva, M. A., Prado, V. F. and Prado, M. A. M. (1997) Effect of protein kinase C activation on the release of [3H]Acetylcholine in the presence of vesamicol. J. Neurochem. 69, 2608-2611
40. Clarizia, A. D., Gomez, M. V., Romano-Silva, M. A., Parsons, S. M., Prado, V. F. and Prado, M. A. (1999) Control of the binding of a vesamicol analog to the vesicular acetylcholine transporter. NeuroReport 10, 2783-2787
41. Clarizia, A. D., Romano-Silva, M. A., Prado, V. F., Gomez, M. V. and Prado, M. A. M. (1998) Role of protein kinase C in the release of [3H]acetylcholine from myenteric plexus treated with vesamicol. Neurosci. Lett. 244, 115-117
42. Efange, S. M., von Hohenberg, K., Khare, A. B., Tu, Z., Mach, R. H. and Parsons, S. M. (2000) Synthesis and biological characterization of stable and radioiodinated (+? )-trans-2-hydroxy-3-{4-(3-iodophenyl)piperidyl}-1,2,3,4- tetrahydronaphthalene (3-IBVM). Nucl. Med. Biol. 27, 749-755
43. Tu, Z., Efange, S. M., Xu, J., Li, S., Jones, L. A., Parsons, S. M. and Mach, R. H. (2009) Synthesis and in vitro and in vivo evaluation of 18F-labeled positron emission tomography (PET) ligands for imaging the vesicular acetylcholine transporter. J. Med. Chem. 52, 1358-1369
44. Kozaka, T., Uno, I., Kitamura, Y., Miwa, D., Ogawa, K. and Shiba, K. (2012) Syntheses and in vitro evaluation of decalinvesamicol analogues as potential imaging probes for vesicular acetylcholine transporter (VAChT). Bioorg. Med. Chem. 20, 4936-4941
45. Grygoruk, A., Fei, H., Daniels, R. W., Miller, B. R., Chen, A., DiAntonio, A. and Krantz, D. E. (2010) Vesicular neurotransmitter transporter trafficking in vivo: moving from cells to flies. Fly 4, 302-305
46. Prado, V. F. and Prado, M. A. (2002) Signals involved in targeting membrane proteins to synaptic vesicles. Cell. Mol. Neurobiol. 22, 565-577
47. Gilmor, M. L., Nash, N. R., Roghani, A., Edwards, R. H., Yi, H., Hersch, S. M. and Levey, A. I. (1996) Expression of the putative vesicular acetylcholine transporter in rat brain and localization in cholinergic synaptic vesicles. J. Neurosci. 16, 2179-2190
48. Liu, Y. and Edwards, R. H. (1997) The role of vesicular transport proteins in synaptic transmission and neural degeneration. Annu. Rev. Neurosci. 20, 125-156
49. Krantz, D. E., Waites, C., Oorschot, V., Liu, Y., Wilson, R. I., Tan, P. K., Klumperman, J. and Edwards, R. H. (2000) A phosphorylation site regulates sorting of the vesicular acetylcholine transporter to dense core vesicles. J. Cell Biol. 149, 379-396
50. Varoqui, H. and Erickson, J. D. (1998) The cytoplasmic tail of the vesicular acetylcholine transporter contains a synaptic vesicle targeting signal. J. Biol. Chem. 273, 9094-9098
51. Tan, P. K., Waites, C., Liu, Y., Krantz, D. E. and Edwards, R. H. (1998) A leucine-based motif mediates the endocytosis of vesicular monoamine and acetylcholine transporters. J. Biol. Chem. 273, 17351-17360
52. Barbosa, Jr, J., Ferreira, L. T., Martins-Silva, C., Santos, M. S., Torres, G. E., Caron, M. G., Gomez, M. V., Ferguson, S. S., Prado, M. A. and Prado, V. F. (2002) Trafficking of the vesicular acetylcholine transporter in SN56 cells: a dynamin-sensitive step and interaction with the AP-2 adaptor complex. J. Neurochem. 82, 1221-1228
53. Ferreira, L. T., Santos, M. S., Kolmakova, N. G., Koenen, J., Barbosa, Jr, J., Gomez, M. V., Guatimosim, C., Zhang, X., Parsons, S. M., Prado, V. F. and Prado, M. A. (2005) Structural requirements for steady-state localization of the vesicular acetylcholine transporter. J. Neurochem. 94, 957-969
54. Santos, M. S., Barbosa, J., Kushmerick, C., Gomez, M. V., Ferguson, S. S. G., Prado, V. F. and Prado, M. A. M. (2001) Visualization and trafficking of the vesicular acetylcholine transporter in living cholinergic cells. J. Neurochem. 78, 37-37
55. Colgan, L., Liu, H., Huang, S. Y. and Liu, Y. J. (2007) Dileucine motif is sufficient for internalization and synaptic vesicle targeting of vesicular acetylcholine transporter. Traffic 8, 512-522
56. Ribeiro, F. M., Alves-Silva, J., Volknandt, W., Martins-Silva, C., Mahmud, H., Wilhelm, A., Gomez, M. V., Rylett, R. J., Ferguson, S. S., Prado, V. F. and Prado, M. A. (2003) The hemicholinium-3 sensitive high affinity choline transporter is internalized by clathrin-mediated endocytosis and is present in endosomes and synaptic vesicles. J. Neurochem. 87, 136-146
57. Ribeiro, F. M., Black, S. A., Cregan, S. P., Prado, V. F., Prado, M. A., Rylett, R. J. and Ferguson, S. S. (2005) Constitutive high-affinity choline transporter endocytosis is determined by a carboxyl-terminal tail dileucine motif. J. Neurochem. 94, 86-96
58. Ribeiro, F. M., Pinthong, M., Black, S. A., Gordon, A. C., Prado, V. F., Prado, M. A., Rylett, R. J. and Ferguson, S. S. (2007) Regulated recycling and plasma membrane recruitment of the high-affinity choline transporter. Eur. J. Neurosci. 26, 3437-3448
59. Sandoval, G. M., Duerr, J. S., Hodgkin, J., Rand, J. B. and Ruvkun, G. (2006) A genetic interaction between the vesicular acetylcholine transporter VAChT/UNC-17 and synaptobrevin/SNB-1 in C. elegans. Nat. Neurosci. 9, 599-601
60. Ribeiro, F. M., Ferreira, L. T., Marion, S., Fontes, S., Gomez, M., Ferguson, S. S., Prado, M. A. and Prado, V. F. (2007) SEC14-like protein 1 interacts with cholinergic transporters. Neurochem. Int. 50, 356-364
61. Terry, Jr, A., Gearhart, D. A., Warner, S. E., Zhang, G., Bartlett, M. G., Middlemore, M. L., Beck, Jr, W. D., Mahadik, S. P. and Waller, J. L. (2007) Oral haloperidol or risperidone treatment in rats: temporal effects on nerve growth factor receptors, cholinergic neurons, and memory performance. Neuroscience 146, 1316-1332
62. Chen, K. H., Reese, E. A., Kim, H. W., Rapoport, S. I. and Rao, J. S. (2011) Disturbed neurotransmitter transporter expression in Alzheimer's disease brain. J. Alzheimers Dis. 26, 755-766
63. Efange, S. M., Garland, E. M., Staley, J. K., Khare, A. B. and Mash, D. C. (1997) Vesicular acetylcholine transporter density and Alzheimer's disease. Neurobiol. Aging 18, 407-413
64. Semmler, A., Frisch, C., Debeir, T., Ramanathan, M., Okulla, T., Klockgether, T. and Heneka, M. T. (2007) Long-term cognitive impairment, neuronal loss and reduced cortical cholinergic innervation after recovery from sepsis in a rodent model. Exp. Neurol. 204, 733-740
65. Li, D. J., Evans, R. G., Yang, Z. W., Song, S. W., Wang, P., Ma, X. J., Liu, C., Xi, T., Su, D. F. and Shen, F. M. (2011) Dysfunction of the cholinergic anti-inflammatory pathway mediates organ damage in hypertension. Hypertension 57, 298-307
66. Smith, R., Chung, H., Rundquist, S., Maat-Schieman, M. L., Colgan, L., Englund, E., Liu, Y. J., Roos, R. A., Faull, R. L., Brundin, P. and Li, J. Y. (2006) Cholinergic neuronal defect without cell loss in Huntington's disease. Hum. Mol. Genet. 15, 3119-3131
67. Edwards, R. H. (2007) The neurotransmitter cycle and quantal size. Neuron 55, 835-858
68. Contant, C., Umbriaco, D., Garcia, S., Watkins, K. C. and Descarries, L. (1996) Ultrastructural characterization of the acetylcholine innervation in adult rat neostriatum. Neuroscience 71, 937-947
69. Duffy, A. M., Zhou, P., Milner, T. A. and Pickel, V. M. (2009) Spatial and intracellular relationships between the alpha7 nicotinic acetylcholine receptor and the vesicular acetylcholine transporter in the prefrontal cortex of rat and mouse. Neuroscience 161, 1091-1103
70. Nagy, P. M. and Aubert, I. (2012) Overexpression of the vesicular acetylcholine transporter increased acetylcholine release in the hippocampus. Neuroscience 218, 1-11
71. de Castro, B. M., De Jaeger, X., Martins-Silva, C., Lima, R. F., Amaral, E., Menezes, C., Lima, P., Neves, C. M. L., Pires, R. G., Gould, T. W. et al. (2009) The vesicular acetylcholine transporter is required for neuromuscular development and function. Mol. Cell. Biol. 29, 5238-5250
72. de Castro, B. M., Pereira, G. S., Magalhaes, V., Rossato, J. I., De Jaeger, X., Martins-Silva, C., Leles, B., Lima, P., Gomez, M. V., Gainetdinov, R. R. et al. (2009) Reduced expression of the vesicular acetylcholine transporter causes learning deficits in mice. Genes Brain Behav. 8, 23-35
73. Lara, A., Damasceno, D. D., Pires, R., Gros, R., Gomes, E. R., Gavioli, M., Lima, R. F., Guimaraes, D., Lima, P., Bueno, Jr, C. R. et al. (2010) Dysautonomia due to reduced cholinergic neurotransmission causes cardiac remodeling and heart failure. Mol. Cell. Biol. 30, 1746-1756
74. Martins-Silva, C., De Jaeger, X., Guzman, M. S., Lima, R. D., Santos, M. S., Kushmerick, C., Gomez, M. V., Caron, M. G., Prado, M. A. and Prado, V. F. (2011) Novel strains of mice deficient for the vesicular acetylcholine transporter: insights on transcriptional regulation and control of locomotor behavior. PLoS ONE 6, e17611
75. Martyn, A. C., De Jaeger, X., Magalhaes, A. C., Kesarwani, R., Goncalves, D. F., Raulic, S., Guzman, M. S., Jackson, M. F., Izquierdo, I., Macdonald, J. F. et al. (2012) Elimination of the vesicular acetylcholine transporter in the forebrain causes hyperactivity and deficits in spatial memory and long-term potentiation. Proc. Natl. Acad. Sci. U.S.A. 109, 17651-17656
76. Guzman, M. S., De Jaeger, X., Raulic, S., Souza, I. A., Li, A. X., Schmid, S., Menon, R. S., Gainetdinov, R. R., Caron, M. G., Bartha, R. et al. (2011) Elimination of the vesicular acetylcholine transporter in the striatum reveals regulation of behaviour by cholinergic-glutamatergic co-transmission. PLoS Biol. 9, e1001194
77. Liu, Y., Peter, D., Roghani, A., Schuldiner, S., Prive, G. G., Eisenberg, D., Brecha, N. and Edwards, R. H. (1992) A cDNA that suppresses MPP+ toxicity encodes a vesicular amine transporter. Cell 70, 539-551
78. Misgeld, T., Burgess, R. W., Lewis, R. M., Cunningham, J. M., Lichtman, J. W. and Sanes, J. R. (2002) Roles of neurotransmitter in synapse formation: development of neuromuscular junctions lacking choline acetyltransferase. Neuron 36, 635-648
79. Brandon, E. P., Lin, W., D'Amour, K. A., Pizzo, D. P., Dominguez, B., Sugiura, Y., Thode, S., Ko, C. P., Thal, L. J., Gage, F. H. and Lee, K. F. (2003) Aberrant patterning of neuromuscular synapses in choline acetyltransferase-deficient mice. J. Neurosci. 23, 539-549
80. De Jaeger, X., Cammarota, M., Prado, M. A., Izquierdo, I., Prado, V. F. and Pereira, G. S. (2012) Decreased acetylcholine release delays the consolidation of object recognition memory. Behav. Brain Res. 238C, 62-68
81. Takamori, S., Holt, M., Stenius, K., Lemke, E. A., Gronborg, M., Riedel, D., Urlaub, H., Schenck, S., Brugger, B., Ringler, P. et al. (2006) Molecular anatomy of a trafficking organelle. Cell 127, 831-846
82. Hasselmo, M. E. and Sarter, M. (2011) Modes and models of forebrain cholinergic neuromodulation of cognition. Neuropsychopharmacology 36, 52-73
83. Sarter, M. and Paolone, G. (2011) Deficits in attentional control: cholinergic mechanisms and circuitry-based treatment approaches. Behav. Neurosci. 125, 825-835
84. Howe, W. M., Ji, J., Parikh, V., Williams, S., Mocaer, E., Trocme-Thibierge, C. and Sarter, M. (2010) Enhancement of attentional performance by selective stimulation of alpha4beta2(*) nAChRs: underlying cholinergic mechanisms. Neuropsychopharmacology 35, 1391-1401
85. Parikh, V. and Sarter, M. (2008) Cholinergic mediation of attention: contributions of phasic and tonic increases in prefrontal cholinergic activity. Ann. N.Y. Acad. Sci. 1129, 225-235
86. Hasselmo, M. E. and Giocomo, L. M. (2006) Cholinergic modulation of cortical function. J. Mol. Neurosci. 30, 133-135
87. Hasselmo, M. E. and Stern, C. E. (2006) Mechanisms underlying working memory for novel information. Trends Cogn. Sci. 10, 487-493
88. Hasselmo, M. E. (2006) The role of acetylcholine in learning and memory. Curr. Opin. Neurobiol. 16, 710-715
89. Ren, J., Qin, C., Hu, F., Tan, J., Qiu, L., Zhao, S., Feng, G. and Luo, M. (2011) Habenula 'cholinergic' neurons corelease glutamate and acetylcholine and activate postsynaptic neurons via distinct transmission modes. Neuron 69, 445-452
90. Nickerson Poulin, A., Guerci, A., El Mestikawy, S. and Semba, K. (2006) Vesicular glutamate transporter 3 immunoreactivity is present in cholinergic basal forebrain neurons projecting to the basolateral amygdala in rat. J. Comp. Neurol. 498, 690-711
91. Schafer, M. K., Varoqui, H., Defamie, N., Weihe, E. and Erickson, J. D. (2002) Molecular cloning and functional identification of mouse vesicular glutamate transporter 3 and its expression in subsets of novel excitatory neurons. J. Biol. Chem. 277, 50734-50748
92. Lee, S., Kim, K. and Zhou, Z. J. (2010) Role of ACh-GABA cotransmission in detecting image motion and motion direction. Neuron 68, 1159-1172
93. Higley, M. J., Gittis, A. H., Oldenburg, I. A., Balthasar, N., Seal, R. P., Edwards, R. H., Lowell, B. B., Kreitzer, A. C. and Sabatini, B. L. (2011) Cholinergic interneurons mediate fast VGluT3-dependent glutamatergic transmission in the striatum. PLoS ONE 6, e19155
94. Hikida, T., Kaneko, S., Isobe, T., Kitabatake, Y., Watanabe, D., Pastan, I. and Nakanishi, S. (2001) Increased sensitivity to cocaine by cholinergic cell ablation in nucleus accumbens. Proc. Natl. Acad. Sci. U.S.A. 98, 13351-13354
95. Kitabatake, Y., Hikida, T., Watanabe, D., Pastan, I. and Nakanishi, S. (2003) Impairment of reward-related learning by cholinergic cell ablation in the striatum. Proc. Natl. Acad. Sci. U.S.A. 100, 7965-7970
96. Threlfell, S., Lalic, T., Platt, N. J., Jennings, K. A., Deisseroth, K. and Cragg, S. J. (2012) Striatal dopamine release is triggered by synchronized activity in cholinergic interneurons. Neuron 75, 58-64
97. Cachope, R., Mateo, Y., Mathur, B. N., Irving, J., Wang, H. L., Morales, M., Lovinger, D. M. and Cheer, J. F. (2012) Selective activation of cholinergic interneurons enhances accumbal phasic dopamine release: setting the tone for reward processing. Cell Rep. 2, 33-41
98. English, D. F., Ibanez-Sandoval, O., Stark, E., Tecuapetla, F., Buzsaki, G., Deisseroth, K., Tepper, J. M. and Koos, T. (2012) GABAergic circuits mediate the reinforcement-related signals of striatal cholinergic interneurons. Nat. Neurosci. 15, 123-130
99. Gallagher, M. and Colombo, P. J. (1995) Ageing: the cholinergic hypothesis of cognitive decline. Curr. Opin. Neurobiol. 5, 161-168
100. Mesulam, M. (2004) The cholinergic lesion of Alzheimer's disease: pivotal factor or side show? Learn. Mem. 11, 43-49
101. Mesulam, M., Shaw, P., Mash, D. and Weintraub, S. (2004) Cholinergic nucleus basalis tauopathy emerges early in the aging-MCI-AD continuum. Ann. Neurol. 55, 815-828
102. Schliebs, R. and Arendt, T. (2006) The significance of the cholinergic system in the brain during aging and in Alzheimer's disease. J. Neural Transm. 113, 1625-1644
103. Schliebs, R., Rossner, S. and Bigl, V. (1996) Immunolesion by 192IgG-saporin of rat basal forebrain cholinergic system: a useful tool to produce cortical cholinergic dysfunction. Prog. Brain Res. 109, 253-264
104. Berson, A., Barbash, S., Shaltiel, G., Goll, Y., Hanin, G., Greenberg, D. S., Ketzef, M., Becker, A. J., Friedman, A. and Soreq, H. (2012) Cholinergic-associated loss of hnRNP-A/B in Alzheimer's disease impairs cortical splicing and cognitive function in mice. EMBO Mol. Med. 4, 730-742
105. Arvidsson, U., Riedl, M., Elde, R. and Meister, B. (1997) Vesicular acetylcholine transporter (VAChT) protein: a novel and unique marker for cholinergic neurons in the central and peripheral nervous systems. J. Comp. Neurol. 378, 454-467
106. Olshansky, B., Sabbah, H. N., Hauptman, P. J. and Colucci, W. S. (2008) Parasympathetic nervous system and heart failure: pathophysiology and potential implications for therapy. Circulation 118, 863-871
107. Hasking, G. J., Esler, M. D., Jennings, G. L., Burton, D., Johns, J. A. and Korner, P. I. (1986) Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation 73, 615-621
108. Nolan, J., Flapan, A. D., Capewell, S., MacDonald, T. M., Neilson, J. M. and Ewing, D. J. (1992) Decreased cardiac parasympathetic activity in chronic heart failure and its relation to left ventricular function. Br. Heart J. 67, 482-485
109. Floras, J. S. (1993) Clinical aspects of sympathetic activation and parasympathetic withdrawal in heart failure. J. Am. Coll. Cardiol. 22, 72A-84A
110. Borovikova, L. V., Ivanova, S., Zhang, M., Yang, H., Botchkina, G. I., Watkins, L. R., Wang, H., Abumrad, N., Eaton, J. W. and Tracey, K. J. (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405, 458-462
111. Kawada, T., Yamazaki, T., Akiyama, T., Li, M., Ariumi, H., Mori, H., Sunagawa, K. and Sugimachi, M. (2006) Vagal stimulation suppresses ischemia-induced myocardial interstitial norepinephrine release. Life Sci. 78, 882-887
112. Kawada, T., Yamazaki, T., Akiyama, T., Shishido, T., Inagaki, M., Uemura, K., Miyamoto, T., Sugimachi, M., Takaki, H. and Sunagawa, K. (2001) In vivo assessment of acetylcholine-releasing function at cardiac vagal nerve terminals. Am. J. Physiol. Heart Circ. Physiol. 281, H139-H145
113. Kessler, W., Traeger, T., Westerholt, A., Neher, F., Mikulcak, M., Muller, A., Maier, S. and Heidecke, C. D. (2006) The vagal nerve as a link between the nervous and immune system in the instance of polymicrobial sepsis. Langenbecks Arch. Surg. 391, 83-87
114. Li, M., Zheng, C., Sato, T., Kawada, T., Sugimachi, M. and Sunagawa, K. (2004) Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats. Circulation 109, 120-124
115. Lopez, N. E., Krzyzaniak, M., Costantini, T. W., De, M. A., Baird, A., Eliceiri, B. P. and Coimbra, R. (2012) Vagal nerve stimulation blocks peritoneal macrophage inflammatory responsiveness after severe burn injury. Shock 38, 294-300
116. Tsutsumi, T., Ide, T., Yamato, M., Kudou, W., Andou, M., Hirooka, Y., Utsumi, H., Tsutsui, H. and Sunagawa, K. (2008) Modulation of the myocardial redox state by vagal nerve stimulation after experimental myocardial infarction. Cardiovasc. Res. 77, 713-721
117. Uemura, K., Li, M., Tsutsumi, T., Yamazaki, T., Kawada, T., Kamiya, A., Inagaki, M., Sunagawa, K. and Sugimachi, M. (2007) Efferent vagal nerve stimulation induces tissue inhibitor of metalloproteinase-1 in myocardial ischemia-reperfusion injury in rabbit. Am. J. Physiol. Heart Circ. Physiol. 293, H2254-H2261
118. Zheng, C., Li, M., Inagaki, M., Kawada, T., Sunagawa, K. and Sugimachi, M. (2005) Vagal stimulation markedly suppresses arrhythmias in conscious rats with chronic heart failure after myocardial infarction. Conf. Proc. IEEE Eng. Med. Biol. Soc. 7, 7072-7075
119. Roy, A., Lara, A., Guimaraes, D., Pires, R., Gomes, E. R., Carter, D. E., Gomez, M. V., Guatimosim, S., Prado, V. F., Prado, M. A. and Gros, R. (2012) An analysis of the myocardial transcriptome in a mouse model of cardiac dysfunction with decreased cholinergic neurotransmission. PLoS ONE 7, e39997
120. LaCroix, C., Freeling, J., Giles, A., Wess, J. and Li, Y. F. (2008) Deficiency of M2 muscarinic acetylcholine receptors increases susceptibility of ventricular function to chronic adrenergic stress. Am. J. Physiol. Heart Circ. Physiol. 294, H810-H820
121. English, B. A., Appalsamy, M., Diedrich, A., Ruggiero, A. M., Lund, D., Wright, J., Keller, N. R., Louderback, K. M., Robertson, D. and Blakely, R. D. (2010) Tachycardia, reduced vagal capacity, and age-dependent ventricular dysfunction arising from diminished expression of the presynaptic choline transporter. Am. J. Physiol. Heart Circ. Physiol. 299, H799-H810
122. Tracey, K. J. (2002) The inflammatory reflex. Nature 420, 853-859
123. Wang, H., Yu, M., Ochani, M., Amella, C. A., Tanovic, M., Susarla, S., Li, J. H., Wang, H., Yang, H., Ulloa, L. et al. (2003) Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421, 384-388
124. Mann, D. L. (2002) Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ. Res. 91, 988-998
125. Wang, H., Liao, H., Ochani, M., Justiniani, M., Lin, X., Yang, L., Al Abed, Y., Wang, H., Metz, C., Miller, E. J. et al. (2004) Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat. Med. 10, 1216-1221
126. Pavlov, V. A., Ochani, M., Yang, L. H., Gallowitsch-Puerta, M., Ochani, K., Lin, X., Levi, J., Parrish, W. R., Rosas-Ballina, M., Czura, C. J. et al. (2007) Selective alpha7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis. Crit. Care Med. 35, 1139-1144
127. van Westerloo, D. J., Giebelen, I. A., Florquin, S., Daalhuisen, J., Bruno, M. J., de Vos, A. F., Tracey, K. J. and van der Poll, T. (2005) The cholinergic anti-inflammatory pathway regulates the host response during septic peritonitis. J. Infect. Dis. 191, 2138-2148
128. Ribeiro Machado, M. P., Rocha, A. M., Oliveira, L. F., Cuba, M. B., Loss, I. O., Castellano, L. C., Silva, M. V., Machado, J. R., Nascentes, G. A., Paiva, L. H. et al. (2012) Autonomic nervous system modulation affects the inflammatory immune response in mice with acute Chagas disease. Exp. Physiol. 97, 1186-1202
129. Masland, R. H., Mills, J. W. and Cassidy, C. (1984) The functions of acetylcholine in the rabbit retina. Proc. R. Soc. London Ser. B 223, 121-139
130. Furness, J. B. (2000) Types of neurons in the enteric nervous system. J. Auton. Nerv. Syst. 81, 87-96
131. Bornstein, J. C., Costa, M. and Grider, J. R. (2004) Enteric motor and interneuronal circuits controlling motility. Neurogastroenterol. Motil. 16, 34-38
132. Barnes, P. J. (2004) Distribution of receptor targets in the lung. Proc. Am. Thorac. Soc. 1, 345-351
133. Wessler, I., Kirkpatrick, C. J. and Racke, K. (1998) Non-neuronal acetylcholine, a locally acting molecule, widely distributed in biological systems: expression and function in humans. Pharmacol. Ther. 77, 59-79
134. Kawashima, K. and Fujii, T. (2000) Extraneuronal cholinergic system in lymphocytes. Pharmacol. Ther. 86, 29-48
135. Fujii, T. and Kawashima, K. (2001) An independent non-neuronal cholinergic system in lymphocytes. Jpn. J. Pharmacol. 85, 11-15
136. Reinheimer, T., Bernedo, P., Klapproth, H., Oelert, H., Zeiske, B., Racke, K. and Wessler, I. (1996) Acetylcholine in isolated airways of rat, guinea pig, and human: species differences in role of airway mucosa. Am. J. Physiol. 270, L722-L728
137. Proskocil, B. J., Sekhon, H. S., Jia, Y., Savchenko, V., Blakely, R. D., Lindstrom, J. and Spindel, E. R. (2004) Acetylcholine is an autocrine or paracrine hormone synthesized and secreted by airway bronchial epithelial cells. Endocrinology 145, 2498-2506
138. Klapproth, H., Reinheimer, T., Metzen, J., Munch, M., Bittinger, F., Kirkpatrick, C. J., Hohle, K. D., Schemann, M., Racke, K. and Wessler, I. (1997) Non-neuronal acetylcholine, a signalling molecule synthezised by surface cells of rat and man. Naunyn Schmiedebergs Arch. Pharmacol. 355, 515-523
139. Kawashima, K., Watanabe, N., Oohata, H., Fujimoto, K., Suzuki, T., Ishizaki, Y., Morita, I. and Murota, S. (1990) Synthesis and release of acetylcholine by cultured bovine arterial endothelial cells. Neurosci. Lett. 119, 156-158
140. Kakinuma, Y., Akiyama, T. and Sato, T. (2009) Cholinoceptive and cholinergic properties of cardiomyocytes involving an amplification mechanism for vagal efferent effects in sparsely innervated ventricular myocardium. FEBS J. 276, 5111-5125
141. Rana, O. R., Schauerte, P., Kluttig, R., Schroder, J. W., Koenen, R. R., Weber, C., Nolte, K. W., Weis, J., Hoffmann, R., Marx, N. and Saygili, E. (2010) Acetylcholine as an age-dependent non-neuronal source in the heart. Auton. Neurosci. 156, 82-89
142. Kawashima, K. and Fujii, T. (2003) The lymphocytic cholinergic system and its contribution to the regulation of immune activity. Life Sci. 74, 675-696
143. Kawashima, K. and Fujii, T. (2004) Expression of non-neuronal acetylcholine in lymphocytes and its contribution to the regulation of immune function. Front. Biosci. 9, 2063-2085
144. Rosas-Ballina, M., Olofsson, P. S., Ochani, M., Valdes-Ferrer, S. I., Levine, Y. A., Reardon, C., Tusche, M. W., Pavlov, V. A., Andersson, U., Chavan, S. et al. (2011) Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 334, 98-101
145. Kawashima, K., Yoshikawa, K., Fujii, Y. X., Moriwaki, Y. and Misawa, H. (2007) Expression and function of genes encoding cholinergic components in murine immune cells. Life Sci. 80, 2314-2319
146. Lips, K. S., Volk, C., Schmitt, B. M., Pfeil, U., Arndt, P., Miska, D., Ermert, L., Kummer, W. and Koepsell, H. (2005) Polyspecific cation transporters mediate luminal release of acetylcholine from bronchial epithelium. Am. J. Respir. Cell Mol. Biol. 33, 79-88
147. Kummer, W., Wiegand, S., Akinci, S., Wessler, I., Schinkel, A. H., Wess, J., Koepsell, H., Haberberger, R. V. and Lips, K. S. (2006) Role of acetylcholine and polyspecific cation transporters in serotonin-induced bronchoconstriction in the mouse. Respir. Res. 7, 65
148. Metzen, J., Bittinger, F., Kirkpatrick, C. J., Kilbinger, H. and Wessler, I. (2003) Proliferative effect of acetylcholine on rat trachea epithelial cells is mediated by nicotinic receptors and muscarinic receptors of the M1-subtype. Life Sci. 72, 2075-2080
149. Improgo, M. R., Tapper, A. R. and Gardner, P. D. (2011) Nicotinic acetylcholine receptor-mediated mechanisms in lung cancer. Biochem. Pharmacol. 82, 1015-1021
150. Pettersson, A., Nilsson, L., Nylund, G., Khorram-Manesh, A., Nordgren, S. and Delbro, D. S. (2009) Is acetylcholine an autocrine/paracrine growth factor via the nicotinic alpha7-receptor subtype in the human colon cancer cell line HT-29? Eur. J. Pharmacol. 609, 27-33
151. Cheng, K., Samimi, R., Xie, G., Shant, J., Drachenberg, C., Wade, M., Davis, R. J., Nomikos, G. and Raufman, J. P. (2008) Acetylcholine release by human colon cancer cells mediates autocrine stimulation of cell proliferation. Am. J. Physiol. Gastrointest. Liver Physiol. 295, G591-G597
152. Gilon, P. and Henquin, J. C. (2001) Mechanisms and physiological significance of the cholinergic control of pancreatic beta-cell function. Endocr. Rev. 22, 565-604
153. Gautam, D., Gavrilova, O., Jeon, J., Pack, S., Jou, W., Cui, Y., Li, J. H. and Wess, J. (2006) Beneficial metabolic effects of M3 muscarinic acetylcholine receptor deficiency. Cell Metab. 4, 363-375
154. Furchgott, R. F. and Zawadzki, J. V. (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288, 373-376
155. Ikeda, C., Morita, I., Mori, A., Fujimoto, K., Suzuki, T., Kawashima, K. and Murota, S. (1994) Phorbol ester stimulates acetylcholine synthesis in cultured endothelial cells isolated from porcine cerebral microvessels. Brain Res. 655, 147-152
156. Kirkpatrick, C. J., Bittinger, F., Unger, R. E., Kriegsmann, J., Kilbinger, H. and Wessler, I. (2001) The non-neuronal cholinergic system in the endothelium: evidence and possible pathobiological significance. Jpn. J. Pharmacol. 85, 24-28
157. Haberberger, R. V., Bodenbenner, M. and Kummer, W. (2000) Expression of the cholinergic gene locus in pulmonary arterial endothelial cells. Histochem. Cell Biol. 113, 379-387
158. Hoover, D. B., Ganote, C. E., Ferguson, S. M., Blakely, R. D. and Parsons, R. L. (2004) Localization of cholinergic innervation in guinea pig heart by immunohistochemistry for high-affinity choline transporters. Cardiovasc. Res. 62, 112-121
159. Crick, S. J., Wharton, J., Sheppard, M. N., Royston, D., Yacoub, M. H., Anderson, R. H. and Polak, J. M. (1994) Innervation of the human cardiac conduction system. A quantitative immunohistochemical and histochemical study. Circulation 89, 1697-1708
160. Okuda, T., Osawa, C., Yamada, H., Hayashi, K., Nishikawa, S., Ushio, T., Kubo, Y., Satou, M., Ogawa, H. and Haga, T. (2012) Transmembrane topology and oligomeric structure of the high-affinity choline transporter. J. Biol. Chem., doi:10.1074/jbc.M112.405027
161. Loewi, O. (1921) Uber humorale Ubertragbarkeit der Herznervenwirkung. I. Pflugers Archiv. 189, 239-242