Cell and Tissue Research

, Volume 376, Issue 1, pp 51–70 | Cite as

Catestatin regulates vesicular quanta through modulation of cholinergic and peptidergic (PACAPergic) stimulation in PC12 cells

  • Bhavani Shankar SahuEmail author
  • Sumana Mahata
  • Keya Bandyopadhyay
  • Manjula Mahata
  • Ennio Avolio
  • Teresa Pasqua
  • Chinmayi Sahu
  • Gautam K. Bandyopadhyay
  • Alessandro Bartolomucci
  • Nicholas J. G. Webster
  • Geert Van Den Bogaart
  • Reiner Fischer-Colbrie
  • Angelo Corti
  • Lee E. Eiden
  • Sushil K. MahataEmail author
Regular Article


We have previously shown that the chromogranin A (CgA)-derived peptide catestatin (CST: hCgA352–372) inhibits nicotine-induced secretion of catecholamines from the adrenal medulla and chromaffin cells. In the present study, we seek to determine whether CST regulates dense core (DC) vesicle (DCV) quanta (catecholamine and chromogranin/secretogranin proteins) during acute (0.5-h treatment) or chronic (24-h treatment) cholinergic (nicotine) or peptidergic (PACAP, pituitary adenylyl cyclase activating polypeptide) stimulation of PC12 cells. In acute experiments, we found that both nicotine (60 μM) and PACAP (0.1 μM) decreased intracellular norepinephrine (NE) content and increased 3H‐NE secretion, with both effects markedly inhibited by co-treatment with CST (2 μM). In chronic experiments, we found that nicotine and PACAP both reduced DCV and DC diameters and that this effect was likewise prevented by CST. Nicotine or CST alone increased expression of CgA protein and together elicited an additional increase in CgA protein, implying that nicotine and CST utilize separate signaling pathways to activate CgA expression. In contrast, PACAP increased expression of CgB and SgII proteins, with a further potentiation by CST. CST augmented the expression of tyrosine hydroxylase (TH) but did not increase intracellular NE levels, presumably due to its inability to cause post-translational activation of TH through serine phosphorylation. Co-treatment of CST with nicotine or PACAP increased quantal size, plausibly due to increased synthesis of CgA, CgB and SgII by CST. We conclude that CST regulates DCV quanta by acutely inhibiting catecholamine secretion and chronically increasing expression of CgA after nicotinic stimulation and CgB and SgII after PACAPergic stimulation.


Chromaffin vesicles Catecholamine PC12 cells Nicotine PACAP Catestatin 



The electron micrographs were taken in the Cellular and Molecular Medicine Electron microscopy core facility at UCSD, which is supported in part by National Institutes of Health Award number S10OD023527. This research was supported by a grant from the Department of Veterans Affairs (I01BX000323 to S.K.M.; I01BX002709 and an SRCS award to N.J.G.W) and the National Institutes of Health (NIH/NIDDK DK102496 to A.B. and MH002386 to L.E.E.). JCSTF-180217 travelling research fellowship to B.S.S. from company of biologists (Cambridge, UK). The Noland Scholarship from the California Institute of Technology supported S.M.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Albillos A, Dernick G, Horstmann H, Almers W, Alvarez de Toledo G, Lindau M (1997) The exocytotic event in chromaffin cells revealed by patch amperometry. Nature 389:509–512CrossRefPubMedGoogle Scholar
  2. Alvarez de Toledo G, Fernandez-Chacon R, Fernandez JM (1993) Release of secretory products during transient vesicle fusion. Nature 363:554–558CrossRefPubMedGoogle Scholar
  3. Angelone T, Quintieri AM, Brar BK, Limchaiyawat PT, Tota B, Mahata SK, Cerra MC (2008) The antihypertensive chromogranin a peptide catestatin acts as a novel endocrine/paracrine modulator of cardiac inotropism and lusitropism. Endocrinology 149:4780–4793CrossRefPubMedPubMedCentralGoogle Scholar
  4. Angelone T, Quintieri AM, Pasqua T, Gentile S, Tota B, Mahata SK, Cerra MC (2012) Phosphodiesterase type-2 and NO-dependent S-nitrosylation mediate the cardioinhibition of the antihypertensive catestatin. Am J Phys Heart Circ Phys 302:H431–H442Google Scholar
  5. Angelone T, Quintieri AM, Pasqua T, Filice E, Cantafio P, Scavello F, Rocca C, Mahata SK, Gattuso A, Cerra MC (2015) The NO stimulator, Catestatin, improves the Frank-Starling response in normotensive and hypertensive rat hearts. Nitric Oxide 50:10–19CrossRefPubMedGoogle Scholar
  6. 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
  7. Bassino E, Fornero S, Gallo MP, Gallina C, Femmino S, Levi R, Tota B, Alloatti G (2015) Catestatin exerts direct protective effects on rat cardiomyocytes undergoing ischemia/reperfusion by stimulating PI3K-Akt-GSK3beta pathway and preserving mitochondrial membrane potential. PLoS One 10:e0119790CrossRefPubMedPubMedCentralGoogle Scholar
  8. Bianco M, Gasparri AM, Colombo B, Curnis F, Girlanda S, Ponzoni M, Bertilaccio MT, Calcinotto A, Sacchi A, Ferrero E, Ferrarini M, Chesi M, Bergsagel PL, Bellone M, Tonon G, Ciceri F, Marcatti M, Caligaris-Cappio F, Corti A (2016) Chromogranin a is preferentially cleaved into proangiogenic peptides in the bone marrow of multiple myeloma patients. Cancer Res 76:1781–1791CrossRefPubMedGoogle Scholar
  9. Biswas N, Gayen J, Mahata M, Su Y, Mahata SK, O'Connor DT (2012) Novel peptide isomer strategy for stable inhibition of catecholamine release: application to hypertension. Hypertension 60:1552–1559CrossRefPubMedPubMedCentralGoogle Scholar
  10. Bittner MA, Aikman RL, Holz RW (2013) A nibbling mechanism for clathrin-mediated retrieval of secretory granule membrane after exocytosis. J Biol Chem 288:9177–9188CrossRefPubMedPubMedCentralGoogle Scholar
  11. Braas KM, May V (1999) Pituitary adenylate cyclase-activating polypeptides directly stimulate sympathetic neuron neuropeptide Y release through PAC(1) receptor isoform activation of specific intracellular signaling pathways. J Biol Chem 274:27702–27710CrossRefPubMedGoogle Scholar
  12. Burgoyne RD, Fisher RJ, Graham ME, Haynes LP, Morgan A (2001) Control of membrane fusion dynamics during regulated exocytosis. Biochem Soc Trans 29:467–472CrossRefPubMedGoogle Scholar
  13. Cheung NS, Basile S, Livett BG (1993) Identification of multiple tachykinins in bovine adrenal medulla using an improved chromatographic procedure. Neuropeptides 24:91–97CrossRefPubMedGoogle Scholar
  14. Colombo B, Curnis F, Foglieni C, Monno A, Arrigoni G, Corti A (2002) Chromogranin A expression in neoplastic cells affects tumor growth and morphogenesis in mouse models. Cancer Res 62:941–946PubMedGoogle Scholar
  15. Corbitt J, Vivekananda J, Wang SS, Strong R (1998) Transcriptional and posttranscriptional control of tyrosine hydroxylase gene expression during persistent stimulation of pituitary adenylate cyclase-activating polypeptide receptors on PC12 cells: regulation by protein kinase A-dependent and protein kinase A-independent pathways. J Neurochem 71:478–486CrossRefPubMedGoogle Scholar
  16. Creutz CE, Harrison JR (1984) Clathrin light chains and secretory vesicle binding proteins are distinct. Nature 308:208–210CrossRefPubMedGoogle Scholar
  17. Delghandi MP, Johannessen M, Moens U (2005) The cAMP signalling pathway activates CREB through PKA, p38 and MSK1 in NIH 3T3 cells. Cell Signal 17:1343–1351CrossRefPubMedGoogle Scholar
  18. Dev NB, Gayen JR, O'Connor DT, Mahata SK (2010) Chromogranin A and the autonomic system: decomposition of heart rate variability by time and frequency domains, along with non-linear characteristics during chromogranin A ablation, with “rescue” by its catestatin. Endocrinology 151:2760–2768CrossRefPubMedPubMedCentralGoogle Scholar
  19. Dhara M, Mohrmann R, Bruns D (2018) v-SNARE function in chromaffin cells. Pflugers Arch 470:169–180CrossRefPubMedGoogle Scholar
  20. Douglas WW, Rubin RP (1961) Mechanism of nicotinic action at the adrenal medulla: calcium as a link in stimulus-secretion coupling. Nature 192:1087–1089CrossRefPubMedGoogle Scholar
  21. Douglas WW, Kanno T, Sampson SR (1967) Effects of acetylcholine and other medullary secretagogues and antagonists on the membrane potential of adrenal chromaffin cells: an analysis employing techniques of tissue culture. J Physiol 188:107–120CrossRefPubMedPubMedCentralGoogle Scholar
  22. Eiden LE (1987) Is chromogranin a prohormone? [news]. Nature 325:301CrossRefPubMedGoogle Scholar
  23. Eiden LE, Emery AC, Zhang L, Smith CB (2018) PACAP signaling in stress: insights from the chromaffin cell. Pflugers Arch 470:79–88CrossRefPubMedGoogle Scholar
  24. Elhamdani A, Azizi F, Artalejo CR (2006) Double patch clamp reveals that transient fusion (kiss-and-run) is a major mechanism of secretion in calf adrenal chromaffin cells: high calcium shifts the mechanism from kiss-and-run to complete fusion. J Neurosci 26:3030–3036CrossRefPubMedGoogle Scholar
  25. 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
  26. Fung MM, Salem RM, Mehtani P, Thomas B, Lu CF, Perez B, Rao F, Stridsberg M, Ziegler MG, Mahata SK, O'Connor DT (2010) Direct vasoactive effects of the chromogranin A (CHGA) peptide catestatin in humans in vivo. Clin Exp Hypertens 32:278–287CrossRefPubMedPubMedCentralGoogle Scholar
  27. Gayen JR, Gu Y, O'Connor DT, Mahata SK (2009a) Global disturbances in autonomic function yield cardiovascular instability and hypertension in the chromogranin a null mouse. Endocrinology 150:5027–5035CrossRefPubMedPubMedCentralGoogle Scholar
  28. Gayen JR, Gu Y, O’Connor DT, Mahata SK (2009b) Global disturbances in autonomic function yield cardiovascular instability and hypertension in the chromogranin A null mouse. Endocrinology 150:5027–5035CrossRefPubMedPubMedCentralGoogle Scholar
  29. Greene LA, Tischler AS (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A 73:2424–2428CrossRefPubMedPubMedCentralGoogle Scholar
  30. Gueorguiev VD, Zeman RJ, Meyer EM, Sabban EL (2000) Involvement of alpha7 nicotinic acetylcholine receptors in activation of tyrosine hydroxylase and dopamine beta-hydroxylase gene expression in PC12 cells. J Neurochem 75:1997–2005CrossRefPubMedGoogle Scholar
  31. Gueorguiev VD, Frenz CM, Ronald KM, Sabban EL (2004) Nicotine and epibatidine triggered prolonged rise in calcium and TH gene transcription in PC12 cells. Eur J Pharmacol 506:37–46CrossRefPubMedGoogle Scholar
  32. Gueorguiev VD, Cheng SY, Sabban EL (2006) Prolonged activation of cAMP-response element-binding protein and ATF-2 needed for nicotine-triggered elevation of tyrosine hydroxylase gene transcription in PC12 cells. J Biol Chem 281:10188–10195CrossRefPubMedGoogle Scholar
  33. Guo X, Wakade AR (1994) Differential secretion of catecholamines in response to peptidergic and cholinergic transmitters in rat adrenals. J Physiol Lond 475:539–545CrossRefPubMedPubMedCentralGoogle Scholar
  34. Hahm SH, Hsu CM, Eiden LE (1998) PACAP activates calcium influx-dependent and -independent pathways to couple met-enkephalin secretion and biosynthesis in chromaffin cells. J Mol Neurosci 11:43–56CrossRefPubMedGoogle Scholar
  35. Hai T, Curran T (1991) Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. Proceedings of the National Academy of Sciences 88(9):3720–3724Google Scholar
  36. Hall FL, Braun RK, Mihara K, Fung YK, Berndt N, Carbonaro-Hall DA, Vulliet PR (1991) Characterization of the cytoplasmic proline-directed protein kinase in proliferative cells and tissues as a heterodimer comprised of p34cdc2 and p58cyclin A. J Biol Chem 266:17430–17440PubMedGoogle Scholar
  37. Halloran SM, Vulliet PR (1994) Microtubule-associated protein kinase-2 phosphorylates and activates tyrosine hydroxylase following depolarization of bovine adrenal chromaffin cells. J Biol Chem 269:30960–30965PubMedGoogle Scholar
  38. Haycock JW (1996) Short- and long-term regulation of tyrosine hydroxylase in chromaffin cells by VIP and PACAP. Ann N Y Acad Sci 805:219–230 discussion 230-211CrossRefPubMedGoogle Scholar
  39. Haycock JW (2002a) Peptide substrates for ERK1/2: structure-function studies of serine 31 in tyrosine hydroxylase. J Neurosci Methods 116:29–34CrossRefPubMedGoogle Scholar
  40. Haycock JW (2002b) Species differences in the expression of multiple tyrosine hydroxylase protein isoforms. J Neurochem 81:947–953CrossRefPubMedGoogle Scholar
  41. Haycock JW, Wakade AR (1992) Activation and multiple-site phosphorylation of tyrosine hydroxylase in perfused rat adrenal glands. J Neurochem 58:57–64CrossRefPubMedGoogle Scholar
  42. Haycock JW, Ahn NG, Cobb MH, Krebs EG (1992) ERK1 and ERK2, two microtubule-associated protein 2 kinases, mediate the phosphorylation of tyrosine hydroxylase at serine-31 in situ. Proc Natl Acad Sci U S A 89:2365–2369CrossRefPubMedPubMedCentralGoogle Scholar
  43. Haycock JW, Lew JY, Garcia-Espana A, Lee KY, Harada K, Meller E, Goldstein M (1998) Role of serine-19 phosphorylation in regulating tyrosine hydroxylase studied with site- and phosphospecific antibodies and site-directed mutagenesis. J Neurochem 71:1670–1675CrossRefPubMedGoogle Scholar
  44. Henkel AW, Kang G, Kornhuber J (2001) A common molecular machinery for exocytosis and the ‘kiss-and-run’ mechanism in chromaffin cells is controlled by phosphorylation. J Cell Sci 114:4613–4620PubMedGoogle Scholar
  45. Hiremagalur B, Nankova B, Nitahara J, Zeman R, Sabban EL (1993) Nicotine increases expression of tyrosine hydroxylase gene. Involvement of protein kinase A-mediated pathway. J Biol Chem 268:23704–23711PubMedGoogle Scholar
  46. Hiremagalur B, Kvetnansky R, Nankova B, Fleischer J, Geertman R, Fukuhara K, Viskupic E, Sabban EL (1994) Stress elicits trans-synaptic activation of adrenal neuropeptide Y gene expression. Brain Res Mol Brain Res 27:138–144CrossRefPubMedGoogle Scholar
  47. Holz RW, Axelrod D (2008) Secretory granule behaviour adjacent to the plasma membrane before and during exocytosis: total internal reflection fluorescence microscopy studies. Acta Physiol (Oxf) 192:303–307CrossRefGoogle Scholar
  48. Imbrogno S, Garofalo F, Cerra MC, Mahata SK, Tota B (2010) The catecholamine release-inhibitory peptide catestatin (chromogranin A344-364) modulates myocardial function in fish. J Exp Biol 213:3636–3643CrossRefPubMedGoogle Scholar
  49. Ishiguro H, Ichino N, Yamada K, Nagatsu T (1997) Nicotine regulates mRNA level of tyrosine hydroxylase gene but not that of nicotinic acetylcholine receptor genes in PC12 cells. Neurosci Lett 228:37–40CrossRefPubMedGoogle Scholar
  50. Isobe K, Yukimasa N, Nakai T, Takuwa Y (1996) Pituitary adenylate cyclase-activating polypeptide induces gene expression of the catecholamine synthesizing enzymes, tyrosine hydroxylase and dopamine beta hydroxylase, through 3′,5′-cyclic adenosine monophosphate- and protein kinase C-dependent mechanisms in cultured porcine adrenal medullary chromaffin cells. Neuropeptides 30:167–175CrossRefPubMedGoogle Scholar
  51. Kakhlon O, Sakya P, Larijani B, Watson R, Tooze SA (2006) GGA function is required for maturation of neuroendocrine secretory granules. EMBO J 25:1590–1602CrossRefPubMedPubMedCentralGoogle Scholar
  52. Kennedy BP, Mahata SK, O'Connor DT, Ziegler MG (1998) Mechanism of cardiovascular actions of the chromogranin A fragment catestatin in vivo. Peptides 19:1241–1248CrossRefPubMedGoogle Scholar
  53. Kirchmair R, Hogue-Angeletti R, Gutierrez J, Fischer-Colbrie R, Winkler H (1993) Secretoneurin—a neuropeptide generated in brain, adrenal medulla and other endocrine tissues by proteolytic processing of secretogranin II (chromogranin C). Neuroscience 53:359–365CrossRefPubMedGoogle Scholar
  54. Kojima M, Ozawa N, Mori Y, Takahashi Y, Watanabe-Kominato K, Shirai R, Watanabe R, Sato K, Matsuyama TA, Ishibashi-Ueda H, Koba S, Kobayashi Y, Hirano T, Watanabe T (2018) Catestatin prevents macrophage-driven atherosclerosis but not arterial injury-induced neointimal hyperplasia. Thromb Haemost 118:182–194CrossRefPubMedGoogle Scholar
  55. Kroesen S, Marksteiner J, Leitner B, Hogue-Angeletti R, Fischer-Colbrie R, Winkler H (1996) Rat brain: distribution of immunoreactivity of PE-11, a peptide derived from chromogranin B. Eur J Neurosci 8:2679–2689CrossRefPubMedGoogle Scholar
  56. Lindgren N, Goiny M, Herrera-Marschitz M, Haycock JW, Hokfelt T, Fisone G (2002) Activation of extracellular signal-regulated kinases 1 and 2 by depolarization stimulates tyrosine hydroxylase phosphorylation and dopamine synthesis in rat brain. Eur J Neurosci 15:769–773CrossRefPubMedGoogle Scholar
  57. Livett BG, Marley PD (1993) Noncholinergic control of adrenal catecholamine secretion. J Anat 183:277–289PubMedPubMedCentralGoogle Scholar
  58. Lopez-Font I, Torregrosa-Hetland CJ, Villanueva J, Gutierrez LM (2010) t-SNARE cluster organization and dynamics in chromaffin cells. J Neurochem 114:1550–1556CrossRefPubMedGoogle Scholar
  59. Mahapatra NR, Mahata M, Datta A, Gerdes H-H, Huttner WB, O’Connor DT, Mahata SK (2000) Neuroendocrine cell type-specific and inducible expression of the chromogranin B gene: crucial role of the proximal promoter. Endocrinology 141:3668–3678CrossRefPubMedGoogle Scholar
  60. Mahapatra NR, O'Connor DT, Vaingankar SM, Hikim AP, Mahata M, Ray S, Staite E, Wu H, Gu Y, Dalton N, Kennedy BP, Ziegler MG, Ross J, Mahata SK (2005) Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog. J Clin Invest 115:1942–1952CrossRefPubMedPubMedCentralGoogle Scholar
  61. Mahata M, Mahata SK, Parmer RJ, O'Connor DT (1996) Vesicular monoamine transport inhibitors. Novel action at calcium channels to prevent catecholamine secretion. Hypertension 28:414–420CrossRefPubMedGoogle Scholar
  62. Mahata SK, O'Connor DT, Mahata M, Yoo SH, Taupenot L, Wu H, Gill BM, Parmer RJ (1997) Novel autocrine feedback control of catecholamine release. A discrete chromogranin A fragment is a noncompetitive nicotinic cholinergic antagonist. J Clin Invest 100:1623–1633CrossRefPubMedPubMedCentralGoogle Scholar
  63. Mahata SK, Mahata M, Parmer RJ, O'Connor DT (1999) Desensitization of catecholamine release: the novel catecholamine release-inhibitory peptide catestatin (chromogranin A344-364) acts at the receptor to prevent nicotinic cholinergic tolerance. J Biol Chem 274:2920–2928CrossRefPubMedGoogle Scholar
  64. Mahata SK, Mahata M, Wakade AR, O'Connor DT (2000) Primary structure and function of the catecholamine release inhibitory peptide catestatin (chromogranin A344-364): identification of amino acid residues crucial for activity. Mol Endocrinol 14:1525–1535PubMedGoogle Scholar
  65. Mahata SK, Mahapatra NR, Mahata M, Wang TC, Kennedy BP, Ziegler MG, O'Connor DT (2003) Catecholamine secretory vesicle stimulus-transcription coupling in vivo. Demonstration by a novel transgenic promoter/photoprotein reporter and inhibition of secretion and transcription by the chromogranin A fragment catestatin. J Biol Chem 278:32058–32067CrossRefPubMedGoogle Scholar
  66. Mahata SK, Mahata M, Wen G, Wong WB, Mahapatra NR, Hamilton BA, O'Connor DT (2004) The catecholamine release-inhibitory “catestatin” fragment of chromogranin A: naturally occurring human variants with different potencies for multiple chromaffin cell nicotinic cholinergic responses. Mol Pharmacol 66:1180–1191CrossRefPubMedGoogle Scholar
  67. Mahata SK, Mahata M, Fung MM, O'Connor DT (2010) Catestatin: a multifunctional peptide from chromogranin A. Regul Pept 162:33–43CrossRefPubMedPubMedCentralGoogle Scholar
  68. Mahata SK, Zheng H, Mahata S, Liu X, Patel KP (2016) Effect of heart failure on catecholamine granule morphology and storage in chromaffin cells. J Endocrinol 230:309–323CrossRefPubMedPubMedCentralGoogle Scholar
  69. 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 9:4150–4157CrossRefPubMedGoogle Scholar
  70. Mazza R, Gattuso A, Mannarino C, Brar BK, Barbieri SF, Tota B, Mahata SK (2008) Catestatin (chromogranin A344-364) is a novel cardiosuppressive agent: inhibition of isoproterenol and endothelin signaling in the frog heart. Am J Physiol Heart Circ Physiol 295:H113–H122CrossRefPubMedPubMedCentralGoogle Scholar
  71. 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
  72. 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
  73. O'Farrell M, Marley PD (1997) Multiple calcium channels are required for pituitary adenylate cyclase- activating polypeptide-induced catecholamine secretion from bovine cultured adrenal chromaffin cells. Naunyn Schmiedeberg's Arch Pharmacol 356:536–542CrossRefGoogle Scholar
  74. Ottesen AH, Carlson CR, Louch WE, Dahl MB, Sandbu RA, Johansen RF, Jarstadmarken H, Bjoras M, Hoiseth AD, Brynildsen J, Sjaastad I, Stridsberg M, Omland T, Christensen G, Rosjo H (2017) Glycosylated chromogranin A in heart failure: implications for processing and cardiomyocyte calcium homeostasis. Circ Heart Fail 10:e003675.
  75. Pasqua T, Mahata S, Bandyopadhyay GK, Biswas A, Perkins GA, Sinha-Hikim AP, Goldstein DS, Eiden LE, Mahata SK (2016) Impact of chromogranin A deficiency on catecholamine storage, catecholamine granule morphology and chromaffin cell energy metabolism in vivo. Cell Tissue Res 363:693–712CrossRefPubMedGoogle Scholar
  76. Patra M, Mahata SK, Padhan DK, Sen M (2016) CCN6 regulates mitochondrial function. J Cell Sci 129:2841–2851CrossRefPubMedGoogle Scholar
  77. Perrelli MG, Tullio F, Angotti C, Cerra MC, Angelone T, Tota B, Alloatti G, Penna C, Pagliaro P (2013) Catestatin reduces myocardial ischaemia/reperfusion injury: involvement of PI3K/Akt, PKCs, mitochondrial KATP channels and ROS signalling. Pflugers Arch 465:1031–1040Google Scholar
  78. Ratti S, Curnis F, Longhi R, Colombo B, Gasparri A, Magni F, Manera E, Metz-Boutigue MH, Corti A (2000) Structure-activity relationships of chromogranin A in cell adhesion. Identification of an adhesion site for fibroblasts and smooth muscle cells. J Biol Chem 275:29257–29263CrossRefPubMedGoogle Scholar
  79. Sahu BS, Manna PT, Edgar JR, Antrobus R, Mahata SK, Bartolomucci A, Borner GHH, Robinson MS (2017) Role of clathrin in dense core vesicle biogenesis. Mol Biol Cell 28:2676–2685CrossRefPubMedPubMedCentralGoogle Scholar
  80. Schubert D, Klier FG (1977) Storage and release of acetylcholine by a clonal cell line. Proc Natl Acad Sci U S A 74:5184–5188CrossRefPubMedPubMedCentralGoogle Scholar
  81. Smith CB, Eiden LE (2012) Is PACAP the major neurotransmitter for stress transduction at the adrenomedullary synapse? J Mol Neurosci 48:403–412CrossRefPubMedPubMedCentralGoogle Scholar
  82. 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
  83. Sugita S (2008) Mechanisms of exocytosis. Acta Physiol (Oxf) 192:185–193CrossRefGoogle Scholar
  84. Suh HW, Hudson PM, McMillian MK, Das KP, Wilson BC, Wu GC, Hong JS (1995) Long-term stimulation of nicotinic receptors is required to increase proenkephalin A mRNA levels and the delayed secretion of [Met5]-enkephalin in bovine adrenal medullary chromaffin cells. J Pharmacol Exp Ther 275:1663–1670PubMedGoogle Scholar
  85. Sutherland C, Alterio J, Campbell DG, Le Bourdelles B, Mallet J, Haavik J, Cohen P (1993) Phosphorylation and activation of human tyrosine hydroxylase in vitro by mitogen-activated protein (MAP) kinase and MAP-kinase-activated kinases 1 and 2. Eur J Biochem 217:715–722CrossRefPubMedGoogle Scholar
  86. Tanaka K, Shibuya I, Nagamoto T, Yamashita 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. Endocrinology 137:956–966CrossRefPubMedGoogle Scholar
  87. Tang K, Wu H, Mahata SK, Taupenot L, Rozansky DJ, Parmer RJ, O'Connor DT (1996) Stimulus-transcription coupling in pheochromocytoma cells. Promoter region-specific activation of chromogranin A biosynthesis. J Biol Chem 271:28382–28390CrossRefPubMedGoogle Scholar
  88. Tang K, Wu H, Mahata SK, Mahata M, Gill BM, Parmer RJ, O'Connor DT (1997) Stimulus coupling to transcription versus secretion in pheochromocytoma cells. Convergent and divergent signal transduction pathways and the crucial roles for route of cytosolic calcium entry and protein kinase C. J Clin Invest 100:1180–1192CrossRefPubMedPubMedCentralGoogle Scholar
  89. Taupenot L, Mahata SK, Wu H, O'Connor DT (1998) Peptidergic activation of transcription and secretion in chromaffin cells. cis and trans signaling determinants of pituitary adenylyl cyclase-activating polypeptide (PACAP). J Clin Invest 101:863–876CrossRefPubMedPubMedCentralGoogle Scholar
  90. Taupenot L, Mahata M, Mahata SK, O’Connor DT (1999) Time-dependent effects of the neuropeptide PACAP on catecholamine secretion. Stimulation and desensitization. Hypertension 34:1152–1162CrossRefPubMedGoogle Scholar
  91. Tischler AS, Perlman RL, Morse GM, Sheard BE (1983) Glucocorticoids increase catecholamine synthesis and storage in PC12 pheochromocytoma cell cultures. J Neurochem 40:364–370CrossRefPubMedGoogle Scholar
  92. Tonshoff C, Hemmick L, Evinger MJ (1997) Pituitary adenylate cyclase activating polypeptide (PACAP) regulates expression of catecholamine biosynthetic enzyme genes in bovine adrenal chromaffin cells. J Mol Neurosci 9:127–140CrossRefPubMedGoogle Scholar
  93. Turquier V, Yon L, Grumolato L, Alexandre D, Fournier A, Vaudry H, Anouar Y (2001) Pituitary adenylate cyclase-activating polypeptide stimulates secretoneurin release and secretogranin II gene transcription in bovine adrenochromaffin cells through multiple signaling pathways and increased binding of pre-existing activator protein-1-like transcription factors. Mol Pharmacol 60:42–52CrossRefPubMedGoogle Scholar
  94. Vaingankar SM, Li Y, Corti A, Biswas N, Gayen JR, O'Connor DT, Mahata SK (2010) Long human CHGA flanking chromosome 14 sequence required for optimal BAC transgenic "rescue" of disease phenotypes in the mouse Chga knockout. Physiol Genomics 41:91–101CrossRefPubMedGoogle Scholar
  95. 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
  96. Vulliet PR, Woodgett JR, Ferrari S, Hardie DG (1985) Characterization of the sites phosphorylated on tyrosine hydroxylase by Ca2+ and phospholipid-dependent protein kinase, calmodulin-dependent multiprotein kinase and cyclic AMP-dependent protein kinase. FEBS Lett 182:335–339CrossRefPubMedGoogle Scholar
  97. Wakade AR (1988) Noncholinergic transmitter(s) maintains secretion of catecholamines from rat adrenal medulla for several hours of continuous stimulation of splanchnic neurons. J Neurochem 50:1302–1308CrossRefPubMedGoogle Scholar
  98. Wakade AR, Wakade TD (1982) Secretion of catecholamines from adrenal gland by a single electrical shock: electronic depolarization of medullary cell membrane. Proc Natl Acad Sci U S A 79:3071–3074CrossRefPubMedPubMedCentralGoogle Scholar
  99. Waschek JA, Pruss RM, Siegel RE, Eiden LE, Bader MF, Aunis D (1987) Regulation of enkephalin, VIP, and chromogranin biosynthesis in actively secreting chromaffin cells. Multiple strategies for multiple peptides. Ann N Y Acad Sci 493:308–323CrossRefPubMedGoogle Scholar
  100. Wen G, Mahata SK, Cadman P, Mahata M, Ghosh S, Mahapatra NR, Rao F, Stridsberg M, Smith DW, Mahboubi P, Schork NJ, O'Connor DT, Hamilton BA (2004) Both rare and common polymorphisms contribute functional variation at CHGA, a regulator of catecholamine physiology. Am J Hum Genet 74:197–207CrossRefPubMedPubMedCentralGoogle Scholar
  101. Westerink RH, Ewing AG (2008) The PC12 cell as model for neurosecretion. Acta Physiol (Oxf) 192:273–285CrossRefGoogle Scholar
  102. 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
  103. Winkler H, Fischer-Colbrie R (1992) The chromogranins a and B: the first 25 years and future perspectives. Neuroscience 49:497–528CrossRefPubMedGoogle Scholar
  104. Winkler H, Westhead E (1980) The molecular organization of adrenal chromaffin granules. Neuroscience 5:1803–1823CrossRefPubMedGoogle Scholar
  105. 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
  106. Winkler H, Sietzen M, Schober M (1987) The life cycle of catecholamine-storing vesicles. Ann N Y Acad Sci 493:3–19CrossRefPubMedGoogle Scholar
  107. Wu H, Mahata SK, Mahata M, Webster NJ, Parmer RJ, O'Connor DT (1995) A functional cyclic AMP response element plays a crucial role in neuroendocrine cell type-specific expression of the secretory granule protein chromogranin A. J Clin Invest 96:568–578CrossRefPubMedPubMedCentralGoogle Scholar
  108. Ying W, Mahata S, Bandyopadhyay GK, Zhou Z, Wollam J, Vu J, Mayoral R, Chi NW, Webster NJG, Corti A, Mahata SK (2018) Catestatin inhibits obesity-induced macrophage infiltration and inflammation in the liver and suppresses hepatic glucose production, leading to improved insulin sensitivity. Diabetes 67:841–848CrossRefPubMedPubMedCentralGoogle Scholar
  109. Zigmond RE, Schwarzschild MA, Rittenhouse AR (1989) Acute regulation of tyrosine hydroxylase by nerve activity and by neurotransmitters via phosphorylation. Annu Rev Neurosci 12:415–461CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Bhavani Shankar Sahu
    • 1
    • 2
    Email author
  • Sumana Mahata
    • 3
  • Keya Bandyopadhyay
    • 2
  • Manjula Mahata
    • 2
  • Ennio Avolio
    • 4
  • Teresa Pasqua
    • 4
  • Chinmayi Sahu
    • 1
  • Gautam K. Bandyopadhyay
    • 2
  • Alessandro Bartolomucci
    • 1
  • Nicholas J. G. Webster
    • 2
    • 5
  • Geert Van Den Bogaart
    • 6
  • Reiner Fischer-Colbrie
    • 7
  • Angelo Corti
    • 8
  • Lee E. Eiden
    • 9
  • Sushil K. Mahata
    • 2
    • 5
    Email author
  1. 1.Department of Integrative Biology and PhysiologyUniversity of MinnesotaMinneapolisUSA
  2. 2.Department of MedicineUniversity of California, San DiegoLa JollaUSA
  3. 3.California Institute of TechnologyPasadenaUSA
  4. 4.University of CalabriaCosenzaItaly
  5. 5.VA San Diego Healthcare SystemSan DiegoUSA
  6. 6.Department of Molecular ImmunologyUniversity of GroningenGroningenNetherlands
  7. 7.Department of PharmacologyMedical University of InnsbruckInnsbruckAustria
  8. 8.IRCCS San Raffaele Scientific InstituteSan Raffaele Vita-Salute UniversityMilanItaly
  9. 9.Section on Molecular Neuroscience, NIMH-IRPBethesdaUSA

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