PACAP signaling in stress: insights from the chromaffin cell

  • Lee E. EidenEmail author
  • Andrew C. Emery
  • Limei Zhang
  • Corey B. Smith
Invited Review


Pituitary adenylate cyclase-activating polypeptide (PACAP) was first identified in hypothalamus, based on its ability to elevate cyclic AMP in the anterior pituitary. PACAP has been identified as the adrenomedullary neurotransmitter in stress through a combination of ex vivo, in vivo, and in cellula experiments over the past two decades. PACAP causes catecholamine secretion, and activation of catecholamine biosynthetic enzymes, during episodes of stress in mammals. Features of PACAP signaling allowing stress transduction at the splanchnicoadrenomedullary synapse have yielded insights into the contrasting roles of acetylcholine's and PACAP's actions as first messengers at the chromaffin cell, via differential release at low and high rates of splanchnic nerve firing, and differential signaling pathway engagement leading to catecholamine secretion and chromaffin cell gene transcription. Secretion stimulated by PACAP, via calcium influx independent of action potential generation, is under active investigation in several laboratories both at the chromaffin cell and within autonomic ganglia of both the parasympathetic and sympathetic nervous systems. PACAP is a neurotransmitter important in stress transduction in the central nervous system as well, and is found at stress-transduction nuclei in brain including the paraventricular nucleus of hypothalamus, the amygdala and extended amygdalar nuclei, and the prefrontal cortex. The current status of PACAP as a master regulator of stress signaling in the nervous system derives fundamentally from the establishment of its role as the splanchnicoadrenomedullary transmitter in stress. Experimental elucidation of PACAP action at this synapse remains at the forefront of understanding PACAP's role in stress signaling throughout the nervous system.


Acetylcholine Catecholamine NCS-Rapgef2 PAC1 Sympathoadrenal axis Sympathetic nervous system 


  1. 1.
    Affolter H-U, Giraud P, Hotchkiss AJ, Eiden LE (1984) Stimulus-secretion-synthesis coupling: a model for cholinergic regulation of enkephalin secretion and gene transcription in adrenomedullary chromaffin cells. In: Fraioli F (ed) Opiate peptides in the periphery. Elsevier, Amsterdam, pp 23–30Google Scholar
  2. 2.
    Ait-Ali D, Samal B, Mustafa T, Eiden LE (2010) Neuropeptides, growth factors and cytokines: a cohort of informational molecules whose expression is up-regulated by the stress-associated slow transmitter PACAP in chromaffin cells. Cell Mol Neurobiol 30:1441–1449CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Anouar Y, Eiden LE (1995) Rapid and long-lasting increase in galanin mRNA levels in rat adrenal medulla following insulin-induced reflex splanchnic nerve stimulation. Neuroendocrinology 62:611–618CrossRefPubMedGoogle Scholar
  4. 4.
    Arimura A (1992) Pituitary adenylate cyclase-activating polypeptide (PACAP): discovery and current status of research. Regul Peptides 37:287–303Google Scholar
  5. 5.
    Arimura A, Shioda S (1995) Pituitary adenylate cyclase activating polypeptide (PACAP) and its receptors: neuroendocrine and endocrine interaction. Front Neuroendocrinol 16:53–88CrossRefPubMedGoogle Scholar
  6. 6.
    Aunis D (1998) Exocytosis in chromaffin cells of the adrenal medulla. Int Rev Cytol 181:213–320CrossRefPubMedGoogle Scholar
  7. 7.
    Beaudet MM, Braas KM, May V (1998) Pituitary adenylate cyclase activating polypeptide (PACAP) expression in sympathetic preganglionic projection neurons to the superior cervical ganglion. J Neurobiol 36:325–336CrossRefPubMedGoogle Scholar
  8. 8.
    Beaudet MM, Parsons RL, Braas KM, May V (2000) Mechanisms mediating pituitary adenylate cyclase-activating polypeptide depolarization of rat sympathetic neurons. J Neurosci 20:7353–7361PubMedGoogle Scholar
  9. 9.
    Borges R, Sala F, Garcia AG (1986) Continuous monitoring of catecholamine release from perfused cat adrenals. J Neurosci Methods 16:289–300CrossRefPubMedGoogle Scholar
  10. 10.
    Braas KM, May V (1996) Pituitary adenylate cyclase-activating polypeptides, PACAP-38 and PACAP-27, regulation of sympathetic neuron catecholamine, and neuropeptide Y expression through activation of type I PACAP/VIP receptor isoforms. Ann N Y Acad Sci 805:204–216CrossRefPubMedGoogle Scholar
  11. 11.
    Brandenburg CA, May V, Braas KM (1997) Identification of endogenous sympathetic neuron pituitary adenylate cyclase-activating polypeptide (PACAP): depolarization regulates production and secretion through induction of multiple neuropeptide transcripts. J Neurosci 17:4045–4055PubMedGoogle Scholar
  12. 12.
    Burnstock G, Ralevic V (2014) Purinergic signaling and blood vessels in health and disease. Pharmacol Rev 66:102–192CrossRefPubMedGoogle Scholar
  13. 13.
    Cannon WB (1929) Organization for physiological homeostasis. Physiol Rev 9:399–431CrossRefGoogle Scholar
  14. 14.
    Chen Y, Hamelink C, Chen Y, Hallenbeck JM, and Eiden LE (2002) Mechanism for neuroprotective effects of PACAP in cerebral ischemic insult in PACAP-deficient mice Washington, DC: Society for Neuroscience . Online Abstract Viewer/Itinerary Planner. 2002Google Scholar
  15. 15.
    Chuang D-M, Costa E (1974) Biosynthesis of tyrosine hydroxylase in rat adrenal medulla after exposure to cold. Proc Natl Acad Sci U S A 71:4570–4574CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Coupland RE (1965) Electron microscopic observations on the structure of the rat adrenal medulla: II. Normal innervation. J Anat 99:255–272PubMedPubMedCentralGoogle Scholar
  17. 17.
    Dai XQ, Ramji A, Liu Y, Li Q, Karpinski E, Chen XZ (2007) Inhibition of TRPP3 channel by amiloride and analogs. Mol Pharmacol 72:1576–1585CrossRefPubMedGoogle Scholar
  18. 18.
    Douglas WW (1968) Stimulus-secretion coupling: the concept and clues from chromaffin and other cells. Br J Pharmacol 34:451–474CrossRefPubMedGoogle Scholar
  19. 19.
    Dzhura I, Chepurny OG, Leech CA, Roe MW, Dzhura E, Xu X, Lu Y, Schwede F, Genieser HG, Smrcka AV, Holz GG (2011) Phospholipase C-epsilon links Epac2 activation to the potentiation of glucose-stimulated insulin secretion from mouse islets of Langerhans. Islets 3:121–128CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Eiden LE, Anouar Y, Hsu C-M, MacArthur L, Hahm SH (1998) Transcription regulation coupled to calcium and protein kinase signaling systems through TRE- and CRE-like sequences in neuropeptide genes. Adv Pharmacol 42:264–269CrossRefPubMedGoogle Scholar
  21. 21.
    Eiden LE, Iacangelo A, Hsu C-M, Hotchkiss AJ, Bader M-F, Aunis D (1987) Chromogranin a synthesis and secretion in chromaffin cells. J Neurochem 49:65–74CrossRefPubMedGoogle Scholar
  22. 22.
    Emery A, Eiden MV, Mustafa T, Eiden LE (2013) GPCR-Gs signaling to ERK is controlled by the cAMP-sensing guanine nucleotide exchange factor NCS/Rapgef2 in neuronal and endocrine cells. Sci Signal 6:ra51CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Emery AC, Alvarez RA, Eiden MV, Xu W, Simeon FG, Eiden LE (2017) Differential Pharmacophore definition of the cAMP binding sites of Neuritogenic cAMP sensor-Rapgef2, protein kinase A, and exchange protein activated by cAMP in neuroendocrine cells using an adenine-based scaffold. ACS Chem NeurosciGoogle Scholar
  24. 24.
    Emery AC, Eiden LE (2012) Signaling through the neuropeptide GPCR PAC1 induces neuritogenesis via a single linear cAMP- and ERK-dependent pathway using a novel cAMP sensor. FASEB J 26:3199–3211CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Emery AC, Eiden MV, Eiden LE (2013) A new site and mechanism of action for the widely used adenylate cyclase inhibitor SQ22,536. Mol Pharmacol 83:95–105CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Fenwick EM, Marty A, Neher E (1982) A patch-clamp study of bovine chromaffin cells and of their sensitivity to acetylcholine. J Physiol 331:577–597CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Fischer-Colbrie R, Chromogranins A (1987) B and C: widespread constituents of secretory vesicles. Ann N Y Acad Sci 493:120–134CrossRefPubMedGoogle Scholar
  28. 28.
    Fischer-Colbrie R, Diez-Guerra J, Emson PC, Winkler H (1986) Bovine chromaffin granules: immunological studies with antisera against neuropeptide Y, [met]enkephalin and bombesin. Neuroscience 18:167–174CrossRefPubMedGoogle Scholar
  29. 29.
    Fischer-Colbrie R, Eskay RL, Eiden LE, Maas D (1992) Transsynaptic regulation of galanin, neurotensin, and substance P in the adrenal medulla: combinatorial control by second-messenger signaling pathways. J Neurochem 59:780–783CrossRefPubMedGoogle Scholar
  30. 30.
    Fischer-Colbrie R, Iacangelo A, Eiden LE (1988) Neural and humoral factors separately regulate neuropeptide Y, enkephalin, and chromogranin A and B mRNA levels in rat adrenal medulla. Proc Natl Acad Sci U S A 85:3240–3244CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Gagnon J, Anini Y (2013) Glucagon stimulates ghrelin secretion through the activation of MAPK and EPAC and potentiates the effect of norepinephrine. Endocrinology 154:666–674CrossRefPubMedGoogle Scholar
  32. 32.
    Garcia AG, Garcia-De-Diego AM, Gandia L, Borges R, Garcia-Sancho J (2006) Calcium signaling and exocytosis in adrenal chromaffin cells. Physiol Rev 86:1093–1131CrossRefPubMedGoogle Scholar
  33. 33.
    Garcia-Palomero E, Cuchillo-Ibanez I, Garcia AG, Renart J, Albillos A, and Montiel C (2000). Greater diversity than previously thought of chromaffin cell Ca2+ channels, derived from mRNA identification studies. FEBS Lett 481:235–239Google Scholar
  34. 34.
    Goldstein DS (2010) Adrenal responses to stress. Cell Mol Neurobiol 30:1433–1440CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Goldstein DS, Kopin IJ (2008) Adrenomedullary, adrenocortical, and sympathoneural responses to stressors: a meta-analysis. Endocr Regul 42:111–119PubMedPubMedCentralGoogle Scholar
  36. 36.
    Guarina L, Vandael DH, Carabelli V, Carbone E (2017) Low pHo boosts burst firing and catecholamine release by blocking TASK-1 and BK channels while preserving Cav1 channels in mouse chromaffin cells. J Physiol 595:2587–2609CrossRefPubMedGoogle Scholar
  37. 37.
    Hamelink C, Tjurmina O, Damadzic R, Young WS, Weihe E, Lee H-W, Eiden LE (2002) Pituitary adenylate cyclase activating polypeptide is a sympathoadrenal neurotransmitter involved in catecholamine regulation and glucohomeostasis. Proc Natl Acad Sci U S A 99:461–466CrossRefPubMedGoogle Scholar
  38. 38.
    Hamelink C, Weihe E, Eiden LE (2003) PACAP: an ‘emergency response’ co-transmitter in the adrenal medulla. In: Vaudry H, Arimura A (eds) Pituitary adenylate cyclase-activating polypeptide. Kluwer-Academic Press, Norwell, Massachusetts, pp 227–250CrossRefGoogle Scholar
  39. 39.
    Heuser JE, Reese TS (1973) Evidence for recycling of synaptic vesicle membrane during transmitter release at the frog neuromuscular junction. J Cell Biol 57:315–344CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Hill J, Chan SA, Kuri B, Smith C (2011) Pituitary adenylate cyclase-activating peptide (PACAP) recruits low voltage-activated T-type calcium influx under acute sympathetic stimulation in mouse adrenal chromaffin cells. J Biol Chem 286:42459–42469CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Hoover DB, Girard BM, Hoover JL, and Parsons RL (2013). PAC receptors mediate positive chronotropic responses to PACAP-27 and VIP in isolated mouse atria. Eur J PharmacolGoogle Scholar
  42. 42.
    Ip NY, Perlman RL, Zigmond RE (1983) Acute transsynaptic regulation of tyrosine 3-monooxygenase activity in the rat superior cervical ganglion: evidence for both cholinergic and noncholinergic mechanisms. Proc Natl Acad Sci U S A 80:2081–2085CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Ip NY, Zigmond RE (2000) Synergistic effects of muscarinic agonists and secretin or vasoactive intestinal peptide on the regulation of tyrosine hydroxylase activity in sympathetic neurons. J Neurobiol 42:14–21CrossRefPubMedGoogle Scholar
  44. 44.
    Jiang SZ, Eiden LE (2016) Activation of the HPA axis and depression of feeding behavior induced by restraint stress are separately regulated by PACAPergic neurotransmission in the mouse. Stress 19:374–382CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Jiang SZ, and Eiden LE. PACAPergic synaptic signaling and circuitry mediating mammalian responses to psychogenic and systemic stressors. In: PACAP2016Google Scholar
  46. 46.
    Jiang SZ, Xu W, Gerfen CR, Eiden MV, Eiden LE (2017) NCS-Rapgef2, the protein product of the neuronal Rapgef2 gene, is a specific activator of D1 dopamine receptor-dependent ERK phosphorylation in mouse brain. eNeuro.
  47. 47.
    Kao SC, Jaiswal RK, Kolch W, Landreth GE (2001) Identification of the mechanisms regulating the differential activation of the MAPK cascade by epidermal growth factor and nerve growth factor in PC12 cells. J Biol Chem 276:18169–18177CrossRefPubMedGoogle Scholar
  48. 48.
    Keiper M, Stope MB, Szatkowski D, Bohm A, Tysack K, Vom Dorp F, Saur O, Oude Weernink PA, Evellin S, Jakobs KH, Schmidt M (2004) Epac− and Ca2+ −controlled activation of Ras and extracellular signal-regulated kinases by Gs-coupled receptors. J Biol Chem 279:46497–46508CrossRefPubMedGoogle Scholar
  49. 49.
    Klevans LR, Gebber GL (1970) Comparison of differential secretion of adrenal catecholamines by splanchnic nerve stimulation and cholinergic agents. J Pharmacol Exp Ther 172:69–76PubMedGoogle Scholar
  50. 50.
    Korthuis RJ (2011) Regulation of vascular tone in skeletal muscle. San Rafael, CA, Morgan & Claypool Life SciencesGoogle Scholar
  51. 51.
    Kuri BA, Chan SA, Smith CB (2009) PACAP regulates immediate catecholamine release from adrenal chromaffin cells in an activity-dependent manner through a protein kinase C-dependent pathway. J Neurochem 110:1214–1225CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Lehmann ML, Mustafa T, Eiden AM, Herkenham M, Eiden LE (2013) PACAP-deficient mice show attenuated corticosterone secretion and fail to develop depressive behavior during chronic social defeat stress. Psychoneuroendocrinology 38:702–715CrossRefPubMedGoogle Scholar
  53. 53.
    Lopez MG, Montiel C, Herrero CJ, Garcia-Palomero E, Mayorgas I, Hernandez-Guijo JM, Villarroya M, Olivares R, Gandia L, McIntosh JM, Olivera BM, Garcia AG (1998) Unmasking the functions of the chromaffin cell alpha7 nicotinic receptor by using short pulses of acetylcholine and selective blockers. Proc Natl Acad Sci U S A 95:14184–14189CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Lopez MG, Villarroya M, Lara B, Martinez SR, Albillos A, Garcia AG, Gandia L (1994) Q- and L-type channels dominate the control of secretion in bovine chromaffin cells. FEBS Lett 349:331–337CrossRefPubMedGoogle Scholar
  55. 55.
    Malhotra RK, Blank M, Wakade TD, Wakade AR (1989) Vasoactive intestinal polypeptide (VIP) serves as another neurotransmitter in the rat adrenal medulla. Regul Peptides 26:168–168CrossRefGoogle Scholar
  56. 56.
    Malhotra RK, Wakade TD, Wakade AR (1988) Comparison of secretion of catecholamines from the rat adrenal medulla during continuous exposure to nicotine, muscarine or excess K. Neuroscience 26:313–320CrossRefPubMedGoogle Scholar
  57. 57.
    Malhotra RK, Wakade TD, Wakade AR (1989) Cross-communication between acetylcholine and VIP in controlling catecholamine secretion by affecting cAMP, inositol triphosphate, protein kinase C, and calcium in rat adrenal medulla. J Neurosci 9:4150–4157PubMedGoogle Scholar
  58. 58.
    Marley PD (1988) Desensitization of the nicotinic secretory response of adrenal chromaffin cells. Trends Pharmacol Sci 9:102–107CrossRefPubMedGoogle Scholar
  59. 59.
    May V, Lutz E, MacKenzie C, Schutz KC, Dozark K, Braas KM (2010) Pituitary adenylate cyclase-activating polypeptide (PACAP)/PAC1HOP1 receptor activation coordinates multiple neurotrophic signaling pathways: Akt activation through phosphatidylinositol 3-kinase gamma and vesicle endocytosis for neuronal survival. J Biol Chem 285:9749–9761CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Merriam LA, Baran CN, Girard BM, Hardwick JC, May V, Parsons RL (2013) Pituitary adenylate cyclase 1 receptor internalization and endosomal signaling mediate the pituitary adenylate cyclase activating polypeptide-induced increase in Guinea pig cardiac neuron excitability. J Neurosci 33:4614–4622CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Miyata A, Arimura A, Dahl RR, Minamino N, Uehara A, Jiang L, Culler MD, Coy DH (1989) Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun 164:567–574CrossRefPubMedGoogle Scholar
  62. 62.
    Mueller RA, Thoenen H, Axelrod J (1970) Inhibition of neuronally induced tyrosine hydroxylase by nicotonic receptor blockade. Eur J Pharmacol 10:51–56CrossRefPubMedGoogle Scholar
  63. 63.
    Mustafa T, Eiden LE (2006) The secretin superfamily: PACAP, VIP and related peptides. In: Lim R (ed) Handbook of neurochemistry and molecular neurobiology: XIII neuroactive peptides and proteins. Springer, Heidelberg, pp 1–36Google Scholar
  64. 64.
    Mustafa T, Grimaldi M, Eiden LE (2007) The hop cassette of the PAC1 receptor confers coupling to Ca2+ elevation required for pituitary adenylate cyclase-activating polypeptide-evoked neurosecretion. J Biol Chem 282:8079–8091CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Mustafa T, Jiang SZ, Eiden AM, Weihe E, Thistlethwaite I, Eiden LE (2015) Impact of PACAP and PAC1 receptor deficiency on the neurochemical and behavioral effects of acute and chronic restraint stress in male C57BL/6 mice. Stress 18(4):408–418CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Mustafa T, Walsh J, Grimaldi M, Eiden LE (2010) PAC1hop receptor activation facilitates catecholamine secretion selectively through 2-APB-sensitive Ca(2+) channels in PC12 cells. Cell Signal 22:1420–1426CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Ozaki N, Shibasaki T, Kashima Y, Miki T, Takahashi K, Ueno H, Sunaga Y, Yano H, Matsuura Y, Iwanaga T, Takai Y, Seino S (2000) cAMP-GEFII is a direct target of cAMP in regulated exocytosis. Nat Cell Biol 2:805–811CrossRefPubMedGoogle Scholar
  68. 68.
    Perez-Alvarez A, Albillos A (2007) Key role of the nicotinic receptor in neurotransmitter exocytosis in human chromaffin cells. J Neurochem 103:2281–2290CrossRefPubMedGoogle Scholar
  69. 69.
    Sandow A (1952) Excitation-contraction coupling in muscular response. Yale J Biol Med 25:176–201PubMedPubMedCentralGoogle Scholar
  70. 70.
    Schmidt M, Evellin S, Weernink PA, von Dorp F, Rehmann H, Lomasney JW, Jakobs KH (2001) A new phospholipase-C-calcium signalling pathway mediated by cyclic AMP and a Rap GTPase. Nat Cell Biol 3:1020–1024CrossRefPubMedGoogle Scholar
  71. 71.
    Seino S, Shibasaki T (2005) PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis. Physiol Rev 85:1303–1342CrossRefPubMedGoogle Scholar
  72. 72.
    Selye H (1973) The evolution of the stress concept. Am Sci 61:692–699PubMedGoogle Scholar
  73. 73.
    Silver DM, Seaton JF, Harrison TS (1968) Adrenal epinephrine and norepinephrine content following denervation and barbiturates. J Surg Res 8:177–181CrossRefPubMedGoogle Scholar
  74. 74.
    Smith C, Moser T, Xu T, Neher E (1998) Cytosolic Ca2+ acts by two separate pathways to modulate the supply of release-competent vesicles in chromaffin cells. Neuron 20:1243–1253CrossRefPubMedGoogle Scholar
  75. 75.
    Smith CB, Eiden LE (2012) Is PACAP the major neurotransmitter for stress transduction at the adrenomedullary synapse? J Mol Neurosci 48:403–412CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Stroth N, Eiden LE (2010) Stress hormone synthesis in mouse hypothalamus and adrenal gland triggered by restraint is dependent on pituitary adenylate cyclase-activating polypeptide signaling. Neuroscience 165:1025–1030CrossRefPubMedGoogle Scholar
  77. 77.
    Stroth N, Hamelink CR, Eiden LE (2007) PACAP-dependent cellular plasticity in the mouse adrenal gland. FASEB J 21:907.906/A1249-c-1250Google Scholar
  78. 78.
    Stroth N, Holighaus Y, Ait-Ali D, Eiden LE (2011) PACAP: a master regulator of neuroendocrine stress circuits and the cellular stress response. Ann N Y Acad Sci 1220:49–59CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Stroth N, Kuri BA, Mustafa T, Chan SA, Smith CB, Eiden LE (2013) PACAP controls adrenomedullary catecholamine secretion and expression of catecholamine biosynthetic enzymes at high splanchnic nerve firing rates characteristic of stress transduction in male mice. Endocrinology 154:330–339CrossRefPubMedGoogle Scholar
  80. 80.
    Stroth N, Liu Y, Aguilera G, Eiden LE (2011) Pituitary adenylate cyclase-activating polypeptide (PACAP) controls stimulus-transcription coupling in the hypothalamic-pituitary-adrenal axis to mediate sustained hormone secretion during stress. J Neuroendocrinol 23:944–955CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Tai TC, Claycomb R, Siddall BJ, Bell RA, Kvetnansky R, Wong DL (2007) Stress-induced changes in epinephrine expression in the adrenal medulla in vivo. J Neurochem 101:1108–1118CrossRefPubMedGoogle Scholar
  82. 82.
    Tai TC, Morita K, Wong DL (2001) Role of Egr-1 in cAMP-dependent protein kinase regulation of the phenylethanolamine N-methyltransferase gene. J Neurochem 76:1851–1859CrossRefPubMedGoogle Scholar
  83. 83.
    Tanaka K, Shibuya I, Nagamoto T, Yamasha H, Kanno T (1996) Pituitary adenylate cyclase-activating polypeptide causes rapid Ca2+ release from intracellular stores and long lasting Ca2+ influx mediated by Na+ influx-dependent membrane depolarization in bovine adrenal chromaffin cells. Endocrinol 137:956–966CrossRefGoogle Scholar
  84. 84.
    Tompkins JD, Parsons RL (2008) Identification of intracellular signaling cascades mediating the PACAP-induced increase in guinea pig cardiac neuron excitability. J Mol Neurosci 36:292–298CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Tsukiyama N, Saida Y, Kakuda M, Shintani N, Hayata A, Morita Y, Tanida M, Tajiri M, Hazama K, Ogata K, Hashimoto H, Baba A (2011) PACAP centrally mediates emotional stress-induced corticosterone responses in mice. Stress 14:368–375CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Vandael DH, Ottaviani MM, Legros C, Lefort C, Guerineau NC, Allio A, Carabelli V, Carbone E (2015) Reduced availability of voltage-gated sodium channels by depolarization or blockade by tetrodotoxin boosts burst firing and catecholamine release in mouse chromaffin cells. J Physiol 593:905–927CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Vitale ML, Seward EP, Trifaro JM (1995) Chromaffin cell cortical actin network dynamics control the size of the release-ready vesicle pool and the initial rate of exocytosis. Neuron 14:353–363CrossRefPubMedGoogle Scholar
  88. 88.
    Waschek JA, Pruss RM, Siegel RE, Eiden LE, Bader M-F, Aunis D (1987) Regulation of enkephalin, VIP and chromogranin A biosynthesis in actively secreting chromaffin cells: multiple strategies for multiple peptides. Ann N Y Acad Sci 493:308–323CrossRefPubMedGoogle Scholar
  89. 89.
    Winkler H (1993) The adrenal chromaffin granule: a model for large dense core vesicles of endocrine and nervous tissue. J Anat 183:237–252PubMedPubMedCentralGoogle Scholar
  90. 90.
    Winkler H, Apps DK, Fischer-Colbrie R (1986) The molecular function of adrenal chromaffin granules: established facts and unresolved topics. Neuroscience 18:261–290CrossRefPubMedGoogle Scholar
  91. 91.
    Zigmond RE (2000) Neuropeptide action in sympathetic ganglia. Evidence for distinct functions in intact and axotomized ganglia. Ann N Y Acad Sci 921:103–108CrossRefPubMedGoogle Scholar

Copyright information

© # Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Lee E. Eiden
    • 1
    Email author
  • Andrew C. Emery
    • 1
  • Limei Zhang
    • 1
    • 2
  • Corey B. Smith
    • 3
  1. 1.Section on Molecular NeuroscienceNational Institute of Mental Health Intramural Research ProgramBethesdaUSA
  2. 2.Department of Physiology, Faculty of MedicineNational Autonomous University of Mexico (UNAM)Mexico CityMexico
  3. 3.Department of Physiology and BiophysicsCase Western Reserve UniversityClevelandUSA

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