Co-Release of Norepinephrine and Acetylcholine by Mammalian Sympathetic Neurons: Regulation by Target-Derived Signaling

  • Jason A. Luther
  • Susan J. Birren


Neurotransmitter expression has long been thought of as a defining phenotypic property of adult neurons. However, it has now been shown that most neurons co-release multiple signaling molecules. Many examples of neurons that co-release a classical transmitter (e.g., acetylcholine, norepinephrine or glutamate) and neuromodulators have been demonstrated, but neurons can also co-release more than one classical transmitter. Defining the mechanisms that determine released transmitter(s) is important for understanding neural function since this largely determines the influence of neural activity. This chapter details evidence showing that mammalian sympathetic neurons co-release acetylcholine (ACh) and norepinephrine (NE). Sympathetic neurons project to body tissues including blood vessels and heart to control functions such as regulation of blood pressure and cardiac output. Transmitter choice in sympathetic neurons is controlled by target-derived, soluble growth factors. Current data suggests that these factors may operate to regulate the relative amounts of ACh and NE released by sympathetic neurons, which may play an important role in homeostatic regulation of essential physiological processes.


Nerve Growth Factor Leukemia Inhibitory Factor Sweat Gland Firing Pattern Sympathetic Neuron 
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.


  1. Anderson RL, Jobling P and Gibbins IL (2001) Development of electrophysiological and morphological diversity in autonomic neurons. J Neurophysiol 86(3):1237--1251PubMedGoogle Scholar
  2. Asmus SE, Parsons S and Landis SC (2000) Developmental changes in the transmitter properties of sympathetic neurons that innervate the periosteum. J Neurosci 20(4):1495--1504PubMedGoogle Scholar
  3. Bamji SX, Majdan M, Pozniak CD, Belliveau DJ, Aloyz R, Kohn J, Causing CG and Miller FD (1998) The p75 neurotrophin receptor mediates neuronal apoptosis and is essential for naturally occurring sympathetic neuron death. J Cell Biol 140(4):911--923PubMedCrossRefGoogle Scholar
  4. Bazan JF (1991) Neuropoietic cytokines in the hematopoietic fold. Neuron 7(2):197--208PubMedCrossRefGoogle Scholar
  5. Bibel M and Barde YA (2000) Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system. Genes Dev 14(23):2919--2937PubMedCrossRefGoogle Scholar
  6. Bierl MA, Jones EE, Crutcher KA and Isaacson LG (2005) “Mature” nerve growth factor is a minor species in most peripheral tissues. Neurosci Lett 380(1-2):133--137PubMedCrossRefGoogle Scholar
  7. Bierl MA and Isaacson LG (2007) Increased NGF proforms in aged sympathetic neurons and their targets. Neurobiol Aging 28(1):122--134PubMedCrossRefGoogle Scholar
  8. Bradley E, Law A, Bell D and Johnson CD (2003) Effects of varying impulse number on cotransmitter contributions to sympathetic vasoconstriction in rat tail artery. Am J Physiol Heart Circ Physiol 284(6):H2007--14PubMedGoogle Scholar
  9. Brodski C, Schnurch H and Dechant G (2000) Neurotrophin-3 promotes the cholinergic differentiation of sympathetic neurons. Proc Natl Acad Sci U S A 97(17):9683--9688PubMedCrossRefGoogle Scholar
  10. Brodski C, Schaubmar A and Dechant G (2002) Opposing functions of GDNF and NGF in the development of cholinergic and noradrenergic sympathetic neurons. Mol Cell Neurosci 19(4):528--538PubMedCrossRefGoogle Scholar
  11. Bunge RP, Rees R, Wood P, Burton H and Ko C (1974) Anatomical and physiological observations on synapses formed on isolated autonomic neurons in tissue culture. Brain Research 66:401--412CrossRefGoogle Scholar
  12. Cai D, Holm JM, Duignan IJ, Zheng J, Xaymardan M, Chin A, Ballard VL, Bella JN and Edelberg JM (2006) BDNF-mediated enhancement of inflammation and injury in the aging heart. Physiol Genomics 24(3):191--197PubMedGoogle Scholar
  13. Cassell JF, Clark AL and McLachlan EM (1986) Characteristics of phasic and tonic sympathetic ganglion cells of the guinea-pig. J Physiol 372:457--483PubMedGoogle Scholar
  14. Chao MV and Hempstead BL (1995) p75 and Trk: a two-receptor system. Trends Neurosci 18(7):321--326PubMedCrossRefGoogle Scholar
  15. Chun LL and Patterson PH (1977) Role of nerve growth factor in the development of rat sympathetic neurons in vitro. I. Survival, growth, and differentiation of catecholamine production. J Cell Biol 75(3):694--704PubMedCrossRefGoogle Scholar
  16. Conforti L, Tohse N and Sperelakis N (1991) Influence of sympathetic innervation on the membrane electrical properties of neonatal rat cardiomyocytes in culture. J Dev Physiol 15(4):237--246PubMedGoogle Scholar
  17. Dale H (1935) Pharmacology and nerve-endings. Proc. R. Soc. Med. 28:319--332Google Scholar
  18. Dixon JE and McKinnon D (1994) Expression of the trk gene family of neurotrophin receptors in prevertebral sympathetic ganglia. Brain Res Dev Brain Res 77(2):177--182PubMedCrossRefGoogle Scholar
  19. Eccles J (1976) From electrical to chemical transmission in the central nervous system. Notes Rec R Soc Lond 30(2):219--230PubMedCrossRefGoogle Scholar
  20. Elfvin LG, Lindh B and Hokfelt T (1993) The chemical neuroanatomy of sympathetic ganglia. Annu Rev Neurosci 16:471--507PubMedCrossRefGoogle Scholar
  21. Elghozi JL and Julien C (2007) Sympathetic control of short-term heart rate variability and its pharmacological modulation. Fundam Clin Pharmacol 21(4):337--347PubMedCrossRefGoogle Scholar
  22. Ernsberger U and Rohrer H (1996) The development of the noradrenergic transmitter phenotype in postganglionic sympathetic neurons. Neurochem Res 21(7):823--829PubMedCrossRefGoogle Scholar
  23. Ernsberger U and Rohrer H (1999) Development of the cholinergic neurotransmitter phenotype in postganglionic sympathetic neurons. Cell Tissue Res 297(3):339--361PubMedCrossRefGoogle Scholar
  24. Ernsberger U (2000) Evidence for an evolutionary conserved role of bone morphogenetic protein growth factors and phox2 transcription factors during noradrenergic differentiation of sympathetic neurons. Induction of a putative synexpression group of neurotransmitter-synthesizing enzymes. Eur J Biochem 267(24):6976--6981PubMedCrossRefGoogle Scholar
  25. Esler M, Rumantir M, Kaye D, Jennings G, Hastings J, Socratous F and Lambert G (2001) Sympathetic nerve biology in essential hypertension. Clin Exp Pharmacol Physiol 28(12):986--989PubMedCrossRefGoogle Scholar
  26. Francis NJ, Asmus SE and Landis SC (1997) CNTF and LIF are not required for the target-directed acquisition of cholinergic and peptidergic properties by sympathetic neurons in vivo. Dev Biol 182(1):76--87PubMedCrossRefGoogle Scholar
  27. Francis NJ and Landis SC (1999) Cellular and molecular determinants of sympathetic neuron development. Annu Rev Neurosci 22:541--566PubMedCrossRefGoogle Scholar
  28. Fukada K (1980) Hormonal control of neurotransmitter choice in sympathetic neurone cultures. Nature 287(5782):553--555PubMedCrossRefGoogle Scholar
  29. Fulop T, Radabaugh S and Smith C (2005) Activity-dependent differential transmitter release in mouse adrenal chromaffin cells. J Neurosci 25(32): 7324--7332PubMedCrossRefGoogle Scholar
  30. Furshpan EJ, MacLeish PR, O’Lague PH and Potter DD (1976) Chemical transmission between rat sympathetic neurons and cardiac myocytes developing in microcultures: evidence for cholinergic, adrenergic, and dual-function neurons. Proc Natl Acad Sci U S A 73(11):4225--4259PubMedCrossRefGoogle Scholar
  31. Furshpan EJ, Landis SC, Matsumoto SG and Potter DD (1986) Synaptic functions in rat sympathetic neurons in microcultures. I. Secretion of norepinephrine and acetylcholine. J Neurosci 6(4):1061--1079PubMedGoogle Scholar
  32. Greene LA, Seeley PJ, Rukenstein A, DiPiazza M and A Howard (1984) Rapid activation of tyrosine hydroxylase in response to nerve growth factor. J Neurochem 42(6):1728--1734Google Scholar
  33. Habecker BA and Landis SC (1994) Noradrenergic regulation of cholinergic differentiation. Science 264(5165):1602--1604PubMedCrossRefGoogle Scholar
  34. Habecker BA, Pennica D and Landis SC (1995) Cardiotrophin-1 is not the sweat gland-derived differentiation factor. Neuroreport 7(1):41--44PubMedGoogle Scholar
  35. Habecker BA, Tresser SJ, Rao MS and Landis SC (1995) Production of sweat gland cholinergic differentiation factor depends on innervation. Dev Biol 167(1):307--316PubMedCrossRefGoogle Scholar
  36. Habecker BA, Symes AJ, Stahl N, Francis NJ, Economides A, Fink JS, Yancopoulos GD and Landis SC (1997) A sweat gland-derived differentiation activity acts through known cytokine signaling pathways. J Biol Chem 272(48):30421--30428PubMedCrossRefGoogle Scholar
  37. Huber LJ and Chao MV (1995) A potential interaction of p75 and trkA NGF receptors revealed by affinity crosslinking and immunoprecipitation. J Neurosci Res 40(4):557--563PubMedCrossRefGoogle Scholar
  38. Jobling P and Gibbins IL (1999) Electrophysiological and morphological diversity of mouse sympathetic neurons. J Neurophysiol 82(5):2747--2764PubMedGoogle Scholar
  39. Kreusser MM, Buss SJ, Krebs J, Kinscherf R, Metz J, Katus HA, Haass M and Backs J (2007) Differential expression of cardiac neurotrophic factors and sympathetic nerve ending abnormalities within the failing heart. J Mol Cell CardiolGoogle Scholar
  40. Kupfermann I (1991) Functional studies of cotransmission. Physiol Rev 71(3):683--732PubMedGoogle Scholar
  41. Lee KF, Li E, Huber LJ, Landis SC, Sharpe AH, Chao MV and Jaenisch R (1992) Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell 69(5):737--749PubMedCrossRefGoogle Scholar
  42. Lockhart ST, Turrigiano GG and Birren SJ (1997) Nerve growth factor modulates synaptic transmission between sympathetic neurons and cardiac myocytes. J Neurosci 17(24):9573--9582PubMedGoogle Scholar
  43. Lu B, Pang PT and Woo NH (2005) The yin and yang of neurotrophin action. Nat Rev Neurosci 6(8):603--614PubMedCrossRefGoogle Scholar
  44. Luther JA and Birren SJ (2006) Nerve growth factor decreases potassium currents and alters repetitive firing in rat sympathetic neurons. J Neurophysiol 96(2):946--958PubMedCrossRefGoogle Scholar
  45. Marder E, Christie AE and Kilman VL (1995) Functional organization of cotransmission systems: lessons from small nervous systems. Invert Neurosci 1(2):105--112PubMedCrossRefGoogle Scholar
  46. Marvin WJ, Jr., Atkins DL, Chittick VL, Lund DD and Hermsmeyer K (1984) In vitro adrenergic and cholinergic innervation of the developing rat myocyte. Circ Res 55(1):49--58PubMedGoogle Scholar
  47. O’Lague PH, Obata K, Claude P, Furshpan EJ and Potter DD (1974) Evidence for cholinergic synapses between dissociated rat sympathetic neurons in cell culture. Proc Natl Acad Sci U S A 71(9):3602--3606PubMedCrossRefGoogle Scholar
  48. O’Lague PH, Furshpan EJ and Potter DD (1978) Studies on rat sympathetic neurons developing in cell culture. II. Synaptic mechanisms. Dev Biol 67(2):404--423PubMedCrossRefGoogle Scholar
  49. O’Lague PH, Potter DD and Furshpan EJ (1978) Studies on rat sympathetic neurons developing in cell culture. I. Growth characteristics and electrophysiological properties. Dev Biol 67(2):384--403PubMedCrossRefGoogle Scholar
  50. O’Lague PH, Potter DD and Furshpan EJ (1978) Studies on rat sympathetic neurons developing in cell culture. III. Cholinergic transmission. Dev Biol 67 (2):424--443PubMedCrossRefGoogle Scholar
  51. Patterson PH and Chun LL (1974) The influence of non-neuronal cells on catecholamine and acetylcholine synthesis and accumulation in cultures of dissociated sympathetic neurons. Proc Natl Acad Sci U S A 71 (9):3607--3610PubMedCrossRefGoogle Scholar
  52. Patterson PH and Chun LL (1977) The induction of acetylcholine synthesis in primary cultures of dissociated rat sympathetic neurons. I. Effects of conditioned medium. Dev Biol 56 (2):263--280PubMedCrossRefGoogle Scholar
  53. Potter DD, Landis SC, Matsumoto SG and Furshpan EJ (1986) Synaptic functions in rat sympathetic neurons in microcultures. II. Adrenergic/cholinergic dual status and plasticity. J Neurosci 6 (4):1080--1098PubMedGoogle Scholar
  54. Potter DD, Matsumoto SG, Landis SC, Sah DW and Furshpan EJ (1986) Transmitter status in cultured sympathetic principal neurons: plasticity, graded expression and diversity. Prog Brain Res 68:103--120PubMedCrossRefGoogle Scholar
  55. Randolph CL, Bierl MA and Isaacson LG (2007) Regulation of NGF and NT-3 protein expression in peripheral targets by sympathetic input. Brain Res 1144:59--69PubMedCrossRefGoogle Scholar
  56. Ro, MS and Landis SC (1990) Characterization of a target-derived neuronal cholinergic differentiation factor. Neuron 5 (6):899--910CrossRefGoogle Scholar
  57. Rao MS, Patterson PH and Landis SC (1992) Multiple cholinergic differentiation factors are present in footpad extracts: comparison with known cholinergic factors. Development 116 (3):731--744PubMedGoogle Scholar
  58. Reichardt LF (2006) Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci 361 (1473):1545--1564PubMedCrossRefGoogle Scholar
  59. Rohrer H (1992) Cholinergic neuronal differentiation factors: evidence for the presence of both CNTF-like and non-CNTF-like factors in developing rat footpad. Development 114 (3):689--698PubMedGoogle Scholar
  60. Saadat S, Sendtner M and Rohrer H (1989) Ciliary neurotrophic factor induces cholinergic differentiation of rat sympathetic neurons in culture. J Cell Biol 108 (5):1807--1816PubMedCrossRefGoogle Scholar
  61. Schafer MK, Schutz B, Weihe E and Eiden LE (1997) Target-independent cholinergic differentiation in the rat sympathetic nervous system. Proc Natl Acad Sci U S A 94 (8):4149--4154PubMedCrossRefGoogle Scholar
  62. Schotzinger RJ and Landis SC (1988) Cholinergic phenotype developed by noradrenergic sympathetic neurons after innervation of a novel cholinergic target in vivo. Nature 335 (6191):637--639PubMedCrossRefGoogle Scholar
  63. Schotzinger RJ and Landis SC (1990) Acquisition of cholinergic and peptidergic properties by sympathetic innervation of rat sweat glands requires interaction with normal target. Neuron 5 (1):91--100PubMedCrossRefGoogle Scholar
  64. Seal RP and Edwards RH (2006) Functional implications of neurotransmitter co-release: glutamate and GABA share the load. Curr Opin Pharmacol 6 (1):114--119PubMedCrossRefGoogle Scholar
  65. Slonimsky JD, Yang B, Hinterneder JM, Nokes EB and Birren SJ (2003) BDNF and CNTF regulate cholinergic properties of sympathetic neurons through independent mechanisms. Mol Cell Neurosci 23 (4):648--660PubMedCrossRefGoogle Scholar
  66. Slonimsky JD, Mattaliano MD, Moon JI, Griffith LC and Birren SJ (2006) Role for calcium/calmodulin-dependent protein kinase II in the p75-mediated regulation of sympathetic cholinergic transmission. Proc Natl Acad Sci U S A 103 (8):2915--2919PubMedCrossRefGoogle Scholar
  67. Stanke M, Duong CV, Pape M, Geissen M, Burbach G, Deller T, Gascan H, Otto C, Parlato R, Schutz G and Rohrer H (2006) Target-dependent specification of the neurotransmitter phenotype: cholinergic differentiation of sympathetic neurons is mediated in vivo by gp 130 signaling. Development 133 (1):141--150PubMedCrossRefGoogle Scholar
  68. Wang HS and McKinnon D (1995) Potassium currents in rat prevertebral and paravertebral sympathetic neurones: control of firing properties. J Physiol 485 ( Pt 2):319--335PubMedGoogle Scholar
  69. Watson AM, Hood SG and May CN (2006) Mechanisms of sympathetic activation in heart failure. Clin Exp Pharmacol Physiol 33 (12):1269--1274PubMedCrossRefGoogle Scholar
  70. Weihe E, Schutz B, Hartschuh W, Anlauf M, Schafer MK and Eiden LE (2005) Coexpression of cholinergic and noradrenergic phenotypes in human and nonhuman autonomic nervous system. J Comp Neurol 492 (3):370--379PubMedCrossRefGoogle Scholar
  71. Woo NH, Teng HK, Siao CJ, Chiaruttini C, Pang PT, Milner TA, Hempstead BL and Lu B (2005) Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat Neurosci 8 (8):1069--1077PubMedCrossRefGoogle Scholar
  72. Wyatt S and Davies AM (1995) Regulation of nerve growth factor receptor gene expression in sympathetic neurons during development. J Cell Biol 130 (6):1435--1446PubMedCrossRefGoogle Scholar
  73. Yamamori T, Fukada K, Aebersold R, Korsching S, Fann MJ and Patterson PH (1989) The cholinergic neuronal differentiation factor from heart cells is identical to leukemia inhibitory factor. Science 246 (4936):1412--1416PubMedCrossRefGoogle Scholar
  74. Yang B, Slonimsky JD and Birren SJ (2002) A rapid switch in sympathetic neurotransmitter release properties mediated by the p75 receptor. Nat Neurosci 5 (6):539--545PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Jason A. Luther
    • 1
  • Susan J. Birren
    • 1
  1. 1.Department of Biology and Volen Center for Complex SystemsBrandeis University, MSWaltham

Personalised recommendations