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VIP and muscarinic synergistic mucin secretion by salivary mucous cells is mediated by enhanced PKC activity via VIP-induced release of an intracellular Ca2+ pool

  • David J. CulpEmail author
  • Z. Zhang
  • R. L. Evans
Signaling and cell physiology
  • 17 Downloads
Part of the following topical collections:
  1. Signaling and cell physiology
  2. Signaling and cell physiology

Abstract

Mucin secretion by salivary mucous glands is mediated predominantly by parasympathetic acetylcholine activation of cholinergic muscarinic receptors via increased intracellular free calcium ([Ca2+]i) and activation of conventional protein kinase C isozymes (cPKC). However, the parasympathetic co-neurotransmitter, vasoactive intestinal peptide (VIP), also initiates secretion, but to a lesser extent. In the present study, cross talk between VIP- and muscarinic-induced mucin secretion was investigated using isolated rat sublingual tubuloacini. VIP-induced secretion is mediated by cAMP-activated protein kinase A (PKA), independently of increased [Ca2+]i. Synergistic secretion between VIP and the muscarinic agonist, carbachol, was demonstrated but only with submaximal carbachol. Carbachol has no effect on cAMP ± VIP. Instead, PKA activated by VIP releases Ca2+ from an intracellular pool maintained by the sarco/endoplasmic reticulum Ca2+-ATPase pump. Calcium release was independent of phospholipase C activity. The resultant sustained [Ca2+]i increase is additive to submaximal, but not maximal carbachol-induced [Ca2+]i. Synergistic mucin secretion was mimicked by VIP plus either phorbol 12-myristate 13-acetate or 0.01 μM thapsigargin, and blocked by the PKC inhibitor, Gö6976. VIP-induced Ca2+ release also promoted store-operated Ca2+ entry. Synergism is therefore driven by VIP-mediated [Ca2+]i augmenting cPKC activity to enhance muscarinic mucin secretion. Additional data suggest ryanodine receptors control VIP/PKA-mediated Ca2+ release from a Ca2+ pool also responsive to maximal carbachol. A working model of muscarinic and VIP control of mucous cell exocrine secretion is presented. Results are discussed in relation to synergistic mechanisms in other secretory cells, and the physiological and therapeutic significance of VIP/muscarinic synergism controlling salivary mucous cell exocrine secretion.

Keywords

Salivary glands Mucous cells Mucins Signal transductions Saliva 

Notes

Acknowledgments

We thank Dr. M. Fallon and Ms. Linda A. Richardson for technical assistance, and Dr. J. Melvin for technical advice and discussions. This work was supported by National Institutes of Health / National Institute of Dental and Craniofacial Research grants DE10480 and DE014730 to D. Culp. The funders had no role in study design, data collection and analysis, decisions to publish, or manuscript preparation.

Author contributions

D. Culp contributed to conception and experimental design of the study, data analysis, interpretation of results, and drafted and critically revised the manuscript; R. L. Evans contributed to the experimental design, data interpretation and critically revised the manuscript; Z. Zhang contributed to the experimental design, data acquisition, data interpretation and drafted and critically revised the manuscript. All authors gave final approval and agree to be accountable for all aspects of the work.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

424_2020_2348_MOESM1_ESM.pdf (70 kb)
ESM 1 (PDF 69 kb)

References

  1. 1.
    Ahuja M, Jha A, Maleth J, Park S, Muallem S (2014) cAMP and Ca2+ signaling in secretory epithelia: crosstalk and synergism. Cell Calcium 55:385–393.  https://doi.org/10.1016/j.ceca.2014.01.006 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Ambudkar I (2018) Calcium signaling defects underlying salivary gland dysfunction. Biochim Biophys Acta Mol Cell Res 1865:1771–1777.  https://doi.org/10.1016/j.bbamcr.2018.07.002 CrossRefPubMedGoogle Scholar
  3. 3.
    Ashton N, Evans RL, Elliott AC, Green R, Argent BE (1993) Regulation of fluid secretion and intracellular messengers in isolated rat pancreatic ducts by acetylcholine. J Physiol 471:549–562.  https://doi.org/10.1113/jphysiol.1993.sp019915 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bhattacharya S, Imbery JF, Ampem PT, Giovannucci DR (2015) Crosstalk between purinergic receptors and canonical signaling pathways in the mouse salivary gland. Cell Calcium 58:589–597.  https://doi.org/10.1016/j.ceca.2015.09.006 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Bou-Hanna C, Berthon B, Combettes L, Claret M, Laboisse CL (1994) Role of calcium in carbachol- and neurotensin-induced mucin exocytosis in a human colonic goblet cell line and cross-talk with the cyclic AMP pathway. Biochem J 299(Pt 2):579–585.  https://doi.org/10.1042/bj2990579 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bradway SD, Bergey EJ, Scannapieco FA, Ramasubbu N, Zawacki S, Levine MJ (1992) Formation of salivary-mucosal pellicle: the role of transglutaminase. Biochem J 284(Pt 2):557–564CrossRefGoogle Scholar
  7. 7.
    Bruce JI, Shuttleworth TJ, Giovannucci DR, Yule DI (2002) Phosphorylation of inositol 1,4,5-trisphosphate receptors in parotid acinar cells. A mechanism for the synergistic effects of cAMP on Ca2+ signaling. J Biol Chem 277:1340–1348.  https://doi.org/10.1074/jbc.M106609200 CrossRefPubMedGoogle Scholar
  8. 8.
    Chaudhuri A, Husain SZ, Kolodecik TR, Grant WM, Gorelick FS (2007) Cyclic AMP-dependent protein kinase and Epac mediate cyclic AMP responses in pancreatic acini. Am J Physiol Gastrointest Liver Physiol 292:G1403–G1410.  https://doi.org/10.1152/ajpgi.00478.2005 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Chen-Engerer HJ, Hartmann J, Karl RM, Yang J, Feske S, Konnerth A (2019) Two types of functionally distinct Ca2+ stores in hippocampal neurons. Nat Commun 10:3223.  https://doi.org/10.1038/s41467-019-11207-8 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Choi YM, Kim SH, Chung S, Uhm DY, Park MK (2006) Regional interaction of endoplasmic reticulum Ca2+ signals between soma and dendrites through rapid luminal Ca2+ diffusion. J Neurosci 26:12127–12136.  https://doi.org/10.1523/JNEUROSCI.3158-06.2006 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Choi JY, Joo NS, Krouse ME, Wu JV, Robbins RC, Ianowski JP, Hanrahan JW, Wine JJ (2007) Synergistic airway gland mucus secretion in response to vasoactive intestinal peptide and carbachol is lost in cystic fibrosis. J Clin Invest 117:3118–3127.  https://doi.org/10.1172/JCI31992 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Coronado R, Morrissette J, Sukhareva M, Vaughan DM (1994) Structure and function of ryanodine receptors. Am J Phys 266:C1485–C1504.  https://doi.org/10.1152/ajpcell.1994.266.6.C1485 CrossRefGoogle Scholar
  13. 13.
    Culp DJ, Richardson LA (1996) Regulation of mucous acinar exocrine secretion with age. J Dent Res 75:575–580.  https://doi.org/10.1177/00220345960750011001 CrossRefPubMedGoogle Scholar
  14. 14.
    Culp DJ, Graham LA, Latchney LR, Hand AR (1991) Rat sublingual gland as a model to study glandular mucous cell secretion. Am J Phys 260:C1233–C1244.  https://doi.org/10.1152/ajpcell.1991.260.6.C1233 CrossRefGoogle Scholar
  15. 15.
    Culp DJ, Luo W, Richardson LA, Watson GE, Latchney LR (1996) Both M1 and M3 receptors regulate exocrine secretion by mucous acini. Am J Phys 271:C1963–C1972CrossRefGoogle Scholar
  16. 16.
    Culp DJ, Zhang Z, Evans RL (2011) Role of calcium and PKC in salivary mucous cell exocrine secretion. J Dent Res 90:1469–1476.  https://doi.org/10.1177/0022034511422817 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Culp DJ, Robinson B, Cash MN, Bhattacharyya I, Stewart C, Cuadra-Saenz G (2015) Salivary mucin 19 glycoproteins: innate immune functions in Streptococcus mutans-induced caries in mice and evidence for expression in human saliva. J Biol Chem 290:2993–3008.  https://doi.org/10.1074/jbc.M114.597906 CrossRefPubMedGoogle Scholar
  18. 18.
    Dehaye JP, Christophe J, Ernst F, Poloczek P, Van Bogaert P (1985) Binding in vitro of vasoactive intestinal peptide on isolated acini of rat parotid glands. Arch Oral Biol 30:827–832CrossRefGoogle Scholar
  19. 19.
    Del Fiacco M, Quartu M, Ekstrom J, Melis T, Boi M, Isola M, Loy F, Serra MP (2015) Effect of the neuropeptides vasoactive intestinal peptide, peptide histidine methionine and substance P on human major salivary gland secretion. Oral Dis 21:216–223.  https://doi.org/10.1111/odi.12249 CrossRefPubMedGoogle Scholar
  20. 20.
    Dickson L, Aramori I, McCulloch J, Sharkey J, Finlayson K (2006) A systematic comparison of intracellular cyclic AMP and calcium signalling highlights complexities in human VPAC/PAC receptor pharmacology. Neuropharmacology 51:1086–1098.  https://doi.org/10.1016/j.neuropharm.2006.07.017 CrossRefPubMedGoogle Scholar
  21. 21.
    DiJulio DH, Watson EL, Pessah IN, Jacobson KL, Ott SM, Buck ED, Singh JC (1997) Ryanodine receptor type III (Ry3R) identification in mouse parotid acini. Properties and modulation of [3H]ryanodine-binding sites. J Biol Chem 272:15687–15696CrossRefGoogle Scholar
  22. 22.
    Ding C, Cong X, Zhang Y, Li SL, Wu LL, Yu GY (2018) Beta-adrenoceptor activation increased VAMP-2 and syntaxin-4 in secretory granules are involved in protein secretion of submandibular gland through the PKA/F-actin pathway. Biosci rep 38.  https://doi.org/10.1042/BSR20171142
  23. 23.
    Dissing S, Nauntofte B, Sten-Knudsen O (1990) Spatial distribution of intracellular, free Ca2+ in isolated rat parotid acini. Pflügers Arch 417:1–12.  https://doi.org/10.1007/bf00370762 CrossRefPubMedGoogle Scholar
  24. 24.
    Dohi T, Yamaki H, Morita K, Kitayama S, Tsuru H, Tsujimoto A (1991) Calcium dependency of adrenergic and muscarinic cholinergic stimulation of mucin release from dog submandibular gland cells. Arch Oral Biol 36:443–449CrossRefGoogle Scholar
  25. 25.
    D'Silva NJ, Jacobson KL, Ott SM, Watson EL (1998) Beta-adrenergic-induced cytosolic redistribution of Rap1 in rat parotid acini: role in secretion. Am J Phys 274:C1667–C1673.  https://doi.org/10.1152/ajpcell.1998.274.6.C1667 CrossRefGoogle Scholar
  26. 26.
    Ekström J, Tobin G (1990) Protein secretion in salivary glands of cats in vivo and in vitro in response to vasoactive intestinal peptide. Acta Physiol Scand 140:95–103.  https://doi.org/10.1111/j.1748-1716.1990.tb08979.x CrossRefPubMedGoogle Scholar
  27. 27.
    Endo M, Praputpittaya C, Fujita K, Kimura F (1987) Effects of vasoactive intestinal polypeptide on acetylcholine stimulation of rat submandibular gland. Endocrinol Jpn 34:387–393CrossRefGoogle Scholar
  28. 28.
    Enyedi P, Fredholm BB, Lundberg JM, Anggard A (1982) Carbachol potentiates the cyclic AMP-stimulating effect of VIP in cat submandibular gland. Eur J Pharmacol 79:139–143.  https://doi.org/10.1016/0014-2999(82)90586-6 CrossRefPubMedGoogle Scholar
  29. 29.
    Ermund A, Trillo-Muyo S, Hansson GC (2018) Assembly, release, and transport of airway mucins in pigs and humans. Ann Am Thorac Soc 15:S159–S163.  https://doi.org/10.1513/AnnalsATS.201804-238AW CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Flynn ER, Bradley KN, Muir TC, McCarron JG (2001) Functionally separate intracellular Ca2+ stores in smooth muscle. J Biol Chem 276:36411–36418.  https://doi.org/10.1074/jbc.M104308200 CrossRefPubMedGoogle Scholar
  31. 31.
    Forstner G, Zhang Y, McCool D, Forstner J (1994) Regulation of mucin secretion in T84 adenocarcinoma cells by forskolin: relationship to Ca2+ and PKC. Am J Phys 266:G606–G612.  https://doi.org/10.1152/ajpgi.1994.266.4.G606 CrossRefGoogle Scholar
  32. 32.
    Foskett JK, Gunter-Smith PJ, Melvin JE, Turner RJ (1989) Physiological localization of an agonist-sensitive pool of Ca2+ in parotid acinar cells. Proc Natl Acad Sci U S A 86:167–171.  https://doi.org/10.1073/pnas.86.1.167 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Fredholm BB, Battig K, Holmen J, Nehlig A, Zvartau EE (1999) Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 51:83–133PubMedGoogle Scholar
  34. 34.
    Fujita-Yoshigaki J, Dohke Y, Hara-Yokoyama M, Kamata Y, Kozaki S, Furuyama S, Sugiya H (1996) Vesicle-associated membrane protein 2 is essential for cAMP-regulated exocytosis in rat parotid acinar cells. The inhibition of cAMP-dependent amylase release by botulinum neurotoxin. B J Biol Chem 271:13130–13134.  https://doi.org/10.1074/jbc.271.22.13130 CrossRefPubMedGoogle Scholar
  35. 35.
    Gibbins HL, Proctor GB, Yakubov GE, Wilson S, Carpenter GH (2014) Concentration of salivary protective proteins within the bound oral mucosal pellicle. Oral Dis 20:707–713.  https://doi.org/10.1111/odi.12194 CrossRefPubMedGoogle Scholar
  36. 36.
    Gomi H, Osawa H, Uno R, Yasui T, Hosaka M, Torii S, Tsukise A (2017) Canine salivary glands: analysis of Rab and SNARE protein expression and SNARE complex formation with diverse tissue properties. J Histochem Cytochem 65:637–653.  https://doi.org/10.1369/0022155417732527 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Grynkiewicz G, Poenie M, Tsien RY (1985) A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260:3440–3450PubMedGoogle Scholar
  38. 38.
    Guerrero-Hernandez A, Sanchez-Vazquez VH, Martinez-Martinez E, Sandoval-Vazquez L, Perez-Rosas NC, Lopez-Farias R, Dagnino-Acosta A (2020) Sarco-endoplasmic reticulum calcium release model based on changes in the luminal calcium content. Adv Exp Med Biol 1131:337–370.  https://doi.org/10.1007/978-3-030-12457-1_14 CrossRefPubMedGoogle Scholar
  39. 39.
    Harmer AR, Gallacher DV, Smith PM (2001) Role of ins(1,4,5)P3, cADP-ribose and nicotinic acid-adenine dinucleotide phosphate in Ca2+ signalling in mouse submandibular acinar cells. Biochem J 353:555–560.  https://doi.org/10.1042/0264-6021:3530555 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Hauk V, Calafat M, Larocca L, Fraccaroli L, Grasso E, Ramhorst R, Leiros CP (2011) Vasoactive intestinal peptide/vasoactive intestinal peptide receptor relative expression in salivary glands as one endogenous modulator of acinar cell apoptosis in a murine model of Sjögren's syndrome. Clin Exp Immunol 166:309–316.  https://doi.org/10.1111/j.1365-2249.2011.04478.x CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Hille B, Billiard J, Babcock DF, Nguyen T, Koh DS (1999) Stimulation of exocytosis without a calcium signal. J Physiol 520(Pt 1):23–31CrossRefGoogle Scholar
  42. 42.
    Imbery JF, Bhattacharya S, Khuder S, Weiss A, Goswamee P, Iqbal AK, Giovannucci DR (2016) cAMP-dependent recruitment of acidic organelles for Ca2+ signaling in the salivary gland. Am J Physiol (Cell Physiol) 311:C697–C709.  https://doi.org/10.1152/ajpcell.00010.2016 CrossRefGoogle Scholar
  43. 43.
    Inoue Y, Kaku K, Kaneko T, Yanaihara N, Kanno T (1985) Vasoactive intestinal peptide binding to specific receptors on rat parotid acinar cells induces amylase secretion accompanied by intracellular accumulation of cyclic adenosine 3′-5′-monophosphate. Endocrinology 116:686–692.  https://doi.org/10.1210/endo-116-2-686 CrossRefPubMedGoogle Scholar
  44. 44.
    Iwabuchi Y, Masuhara T (1994) Effects of vasoactive intestinal peptide and its homologues on the noradrenaline-mediated secretion of fluid and protein from the rat submandibular gland. Gen Pharmac 27(7):1427–1434CrossRefGoogle Scholar
  45. 45.
    Iwabuchi Y, Masuhara T (1995) Effects of vasoactive intestinal peptide and its homologues on the acetylcholine-mediated secretion of fluid and protein from the rat submandibular gland. Gen Pharmacol 26:961–970CrossRefGoogle Scholar
  46. 46.
    Jones LC, Moussa L, Fulcher ML, Zhu Y, Hudson EJ, O'Neal WK, Randell SH, Lazarowski ER, Boucher RC, Kreda SM (2012) VAMP8 is a vesicle SNARE that regulates mucin secretion in airway goblet cells. J Physiol 590:545–562.  https://doi.org/10.1113/jphysiol.2011.222091 CrossRefPubMedGoogle Scholar
  47. 47.
    Jung SR, Hille B, Nguyen TD, Koh DS (2010) Cyclic AMP potentiates Ca2+-dependent exocytosis in pancreatic duct epithelial cells. J Gen Physiol 135:527–543.  https://doi.org/10.1085/jgp.200910355 CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Kase H, Wakui M, Petersen OH (1991) Stimulatory and inhibitory actions of VIP and cyclic AMP on cytoplasmic Ca2+ signal generation in pancreatic acinar cells. Pflügers Arch 419:668–670.  https://doi.org/10.1007/bf00370314 CrossRefPubMedGoogle Scholar
  49. 49.
    Kondo Y, Melvin JE, Catalan MA (2019) Physiological cAMP-elevating secretagogues differentially regulate fluid and protein secretions in mouse submandibular and sublingual glands. Am J Physiol (Cell Physiol) 316:C690–C697.  https://doi.org/10.1152/ajpcell.00421.2018 CrossRefGoogle Scholar
  50. 50.
    Kong H, Jones PP, Koop A, Zhang L, Duff HJ, Chen SR (2008) Caffeine induces Ca2+ release by reducing the threshold for luminal Ca2+ activation of the ryanodine receptor. Biochem J 414:441–452.  https://doi.org/10.1042/BJ20080489 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Kusakabe T, Matsuda H, Gono Y, Kawakami T, Kurihara K, Tsukuda M, Takenaka T (1998) Distribution of VIP receptors in the human submandibular gland: an immunohistochemical study. Histol Histopathol 13:373–378.  https://doi.org/10.14670/HH-13.373 CrossRefPubMedGoogle Scholar
  52. 52.
    Larsson O, Olgart L (1989) The enhancement of carbachol-induced salivary secretion by VIP and CGRP in rat parotid-gland is mimicked by forskolin. Acta Physiol Scand 137:231–236.  https://doi.org/10.1111/j.1748-1716.1989.tb08743.x CrossRefPubMedGoogle Scholar
  53. 53.
    Lee BS, Sessanna S, Laychock SG, Rubin RP (2002) Expression and cellular localization of a modified type 1 ryanodine receptor and L-type channel proteins in non-muscle cells. J Membr Biol 189:181–190.  https://doi.org/10.1007/s00232-002-1012-x CrossRefPubMedGoogle Scholar
  54. 54.
    Li D, Jiao J, Shatos MA, Hodges RR, Dartt DA (2013) Effect of VIP on intracellular [Ca2+], extracellular regulated kinase 1/2, and secretion in cultured rat conjunctival goblet cells. Invest Ophthalmol Vis Sci 54:2872–2884.  https://doi.org/10.1167/iovs.12-11264 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Li JM, Darlak KA, Southerland L, Hossain MS, Jaye DL, Josephson CD, Rosenthal H, Waller EK (2013) VIPhyb, an antagonist of vasoactive intestinal peptide receptor, enhances cellular antiviral immunity in murine cytomegalovirus infected mice. PLoS One 8:e63381.  https://doi.org/10.1371/journal.pone.0063381 CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Lin WK, Bolton EL, Cortopassi WA, Wang Y, O'Brien F, Maciejewska M, Jacobson MP, Garnham C, Ruas M, Parrington J, Lei M, Sitsapesan R, Galione A, Terrar DA (2017) Synthesis of the Ca2+-mobilizing messengers NAADP and cADPR by intracellular CD38 enzyme in the mouse heart: role in beta-adrenoceptor signaling. J Biol Chem 292:13243–13257.  https://doi.org/10.1074/jbc.M117.789347 CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Liu H, Kabrah A, Ahuja M, Muallem S (2019) CRAC channels in secretory epithelial cell function and disease. Cell Calcium 78:48–55.  https://doi.org/10.1016/j.ceca.2018.12.010 CrossRefPubMedGoogle Scholar
  58. 58.
    Lodde BM, Mineshiba F, Wang J, Cotrim AP, Afione S, Tak PP, Baum BJ (2006) Effect of human vasoactive intestinal peptide gene transfer in a murine model of Sjögren's syndrome. Ann Rheum Dis 65:195–200.  https://doi.org/10.1136/ard.2005.038232 CrossRefPubMedGoogle Scholar
  59. 59.
    Lundberg JM (1982) Vasoactive intestinal polypeptide enhances muscarinic ligand binding in cat submandibular salivary gland. Nature 295:147–149.  https://doi.org/10.1038/295147a0 CrossRefPubMedGoogle Scholar
  60. 60.
    Lundberg JM, Anggard A, Fahrenkrug J, Hokfelt T, Mutt V (1980) Vasoactive intestinal polypeptide in cholinergic neurons of exocrine glands: functional significance of coexisting transmitters for vasodilation and secretion. Proc Natl Acad Sci U S A 77:1651–1655.  https://doi.org/10.1073/pnas.77.3.1651 CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Lundberg JM, Anggard A, Fahrenkrug J (1982) Complementary role of vasoactive intestinal polypeptide (VIP) and acetylcholine for cat submandibular gland blood flow and secretion. Acta Physiol Scand 114:329–337.  https://doi.org/10.1111/j.1748-1716.1982.tb06992.x CrossRefPubMedGoogle Scholar
  62. 62.
    Luo W, Latchney LR, Culp DJ (2001) G-protein coupling to M1 and M3 muscarinic receptors in sublingual glands. Am J Physiol Gastrointest Liver Physiol 280:C884–C896CrossRefGoogle Scholar
  63. 63.
    Martiny-Baron G, Kazanietz MG, Mischak H, Blumberg PM, Kochs G, Hug H, Marme D, Schachtele C (1993) Selective inhibition of protein kinase C isozymes by the indolocarbazole Go6976. J Biol Chem 268:9194–9197PubMedGoogle Scholar
  64. 64.
    Mauduit P, Herman G, Rossignol B (1987) Newly synthesized protein secretion in rat lacrimal gland: post-second messenger synergism. Am J Phys 253:C514–C524.  https://doi.org/10.1152/ajpcell.1987.253.4.C514 CrossRefGoogle Scholar
  65. 65.
    Melvin JE, Culp DJ (2004) Salivary gland physiology. In: Williams JA (ed) Encyclopedia of gastroenterology. Academic Press, Inc., San Diego, pp 318–325CrossRefGoogle Scholar
  66. 66.
    Melvin JE, Koek L, Zhang GH (1991) A capacitative Ca2+ influx is required for sustained fluid secretion in sublingual mucous acini. Am J Physiol 261:G1043–G1050PubMedGoogle Scholar
  67. 67.
    Messenger SW, Falkowski MA, Thomas DD, Jones EK, Hong W, Gaisano HY, Boulis NM, Groblewski GE (2014) Vesicle associated membrane protein 8 (VAMP8)-mediated zymogen granule exocytosis is dependent on endosomal trafficking via the constitutive-like secretory pathway. J Biol Chem 289:28040–28053.  https://doi.org/10.1074/jbc.M114.593913 CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Milne RW, Dawes C (1973) The relative contributions of different salivary glands to the blood group activity of whole saliva in humans. Vox Sang 25:298–307CrossRefGoogle Scholar
  69. 69.
    Moreira JE, Tabak LA, Bedi GS, Culp DJ, Hand AR (1989) Light and electron microscopic immunolocalization of rat submandibular gland mucin glycoprotein and glutamine/glutamic acid-rich proteins. J Histochem Cytochem 37:515–528.  https://doi.org/10.1177/37.4.2926128 CrossRefPubMedGoogle Scholar
  70. 70.
    Morzel M, Siying T, Brignot H, Lherminier J (2014) Immunocytological detection of salivary mucins (MUC5B) on the mucosal pellicle lining human epithelial buccal cells. Microsc Res Tech 77:453–457.  https://doi.org/10.1002/jemt.22366 CrossRefPubMedGoogle Scholar
  71. 71.
    Muthumariappan S, Ng WC, Adine C, Ng KK, Davoodi P, Wang CH, Ferreira JN (2019) Localized delivery of pilocarpine to hypofunctional salivary glands through electrospun nanofiber mats: An ex vivo and in vivo study. Int J Mol Sci:20.  https://doi.org/10.3390/ijms20030541 CrossRefGoogle Scholar
  72. 72.
    Nakahari T, Fujiwara S, Shimamoto C, Kojima K, Katsu K, Imai Y (2002) cAMP modulation of Ca2+-regulated exocytosis in ACh-stimulated antral mucous cells of Guinea pig. Am J Physiol Gastrointest Liver Physiol 282:G844–G856.  https://doi.org/10.1152/ajpgi.00300.2001 CrossRefPubMedGoogle Scholar
  73. 73.
    Ozawa T (2010) Modulation of ryanodine receptor Ca2+ channels. Mol Med Rep 3:199–204.  https://doi.org/10.3892/mmr_00000240 CrossRefPubMedGoogle Scholar
  74. 74.
    Pedersen AM, Dissing S, Fahrenkrug J, Hannibal J, Reibel J, Nauntofte B (2000) Innervation pattern and Ca2+ signalling in labial salivary glands of healthy individuals and patients with primary Sjögren's syndrome (pSS). J Oral Pathol Med 29:97–109.  https://doi.org/10.1034/j.1600-0714.2000.290301.x CrossRefPubMedGoogle Scholar
  75. 75.
    Pedersen AML, Sorensen CE, Proctor GB, Carpenter GH, Ekstrom J (2018) Salivary secretion in health and disease. J Oral Rehabil 45:730–746.  https://doi.org/10.1111/joor.12664 CrossRefPubMedGoogle Scholar
  76. 76.
    Peng S, Petersen OH (2019) One or two Ca2+ stores in the neuronal endoplasmic reticulum? Trends Neurosci 42:755–757.  https://doi.org/10.1016/j.tins.2019.09.003 CrossRefPubMedGoogle Scholar
  77. 77.
    Perez-Vilar J (2007) Mucin granule intraluminal organization. Am J Respir Cell Mol Biol 36:183–190.  https://doi.org/10.1165/rcmb.2006-0291TR CrossRefPubMedGoogle Scholar
  78. 78.
    Petersen OH, Courjaret R, Machaca K (2017) Ca2+ tunnelling through the ER lumen as a mechanism for delivering Ca2+ entering via store-operated Ca2+ channels to specific target sites. J Physiol 595:2999–3014.  https://doi.org/10.1113/JP272772 CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Pinkstaff CA (1980) The cytology of salivary glands. Int Rev Cytol 63:141–261CrossRefGoogle Scholar
  80. 80.
    Quissell DO, Barzen KA, Lafferty JL (1981) Role of calcium and cAMP in the regulation of rat submandibular mucin secretion. Am J Phys 241:C76–C85.  https://doi.org/10.1152/ajpcell.1981.241.1.C76 CrossRefGoogle Scholar
  81. 81.
    Rainbow RD, Macmillan D, McCarron JG (2009) The sarcoplasmic reticulum Ca2+ store arrangement in vascular smooth muscle. Cell Calcium 46:313–322.  https://doi.org/10.1016/j.ceca.2009.09.001 CrossRefPubMedGoogle Scholar
  82. 82.
    Ramos-Alvarez I, Lee L, Jensen RT (2019) Cyclic AMP-dependent protein kinase A and EPAC mediate VIP and secretin stimulation of PAK4 and activation of Na+, K+-ATPase in pancreatic acinar cells. Am J Physiol Gastrointest Liver Physiol 316:G263–G277.  https://doi.org/10.1152/ajpgi.00275.2018 CrossRefPubMedGoogle Scholar
  83. 83.
    Robichaux WG 3rd, Cheng X (2018) Intracellular cAMP sensor EPAC: physiology, pathophysiology, and therapeutics development. Physiol Rev 98:919–1053.  https://doi.org/10.1152/physrev.00025.2017 CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Saino T, Watson EL (2009) Inhibition of serine/threonine phosphatase enhances arachidonic acid-induced [Ca2+]i via protein kinase a. Am J Physiol (Cell Physiol) 296:C88–C96.  https://doi.org/10.1152/ajpcell.00281.2008 CrossRefGoogle Scholar
  85. 85.
    Sato K, Ohsaga A, Oshiro T, Ito S, Maruyama Y (2002) Involvement of GTP-binding protein in pancreatic cAMP-mediated exocytosis. Pflügers Arch 443:394–398.  https://doi.org/10.1007/s004240100711 CrossRefPubMedGoogle Scholar
  86. 86.
    Scott J, Baum BJ (1985) Involvement of cyclic AMP and calcium in exocrine protein secretion induced by vasoactive intestinal polypeptide in rat parotid cells. Biochim Biophys Acta 847:255–262CrossRefGoogle Scholar
  87. 87.
    Shah AU, Grant WM, Latif SU, Mannan ZM, Park AJ, Husain SZ (2008) Cyclic AMP accelerates calcium waves in pancreatic acinar cells. Am J Physiol Gastrointest Liver Physiol 294:G1328–G1334.  https://doi.org/10.1152/ajpgi.00440.2007 CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Shimomura H, Imai A, Nashida T (2004) Evidence for the involvement of cAMP-GEF (Epac) pathway in amylase release from the rat parotid gland. Arch Biochem Biophys 431:124–128.  https://doi.org/10.1016/j.abb.2004.07.021 CrossRefPubMedGoogle Scholar
  89. 89.
    Shimura S, Sasaki T, Ikeda K, Sasaki H (1985) Takishima T (1988) VIP augments cholinergic-induced glycoconjugate secretion in tracheal submucosal glands. J Appl Physiol 65:2537–2544.  https://doi.org/10.1152/jappl.1988.65.6.2537 CrossRefGoogle Scholar
  90. 90.
    Soltoff SP, Hedden L (2010) Isoproterenol and cAMP block ERK phosphorylation and enhance [Ca2+]i increases and oxygen consumption by muscarinic receptor stimulation in rat parotid and submandibular acinar cells. J Biol Chem 285:13337–13348.  https://doi.org/10.1074/jbc.M110.112094 CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Stoeckelhuber M, Scherer EQ, Janssen KP, Slotta-Huspenina J, Loeffelbein DJ, Rohleder NH, Nieberler M, Hasler R, Kesting MR (2012) The human submandibular gland: Immunohistochemical analysis of SNAREs and cytoskeletal proteins. J Histochem Cytochem 60:110–120.  https://doi.org/10.1369/0022155411432785 CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Stojic D, Pesic S, Radenkovic M, Popovic-Roganovic J, Pesic Z, Grbovic L (2007) Responses of the human submandibular artery to ACh and VIP. J Dent Res 86:565–570.  https://doi.org/10.1177/154405910708600615 CrossRefPubMedGoogle Scholar
  93. 93.
    Straub SV, Giovannucci DR, Yule DI (2000) Calcium wave propagation in pancreatic acinar cells: functional interaction of inositol 1,4,5-trisphosphate receptors, ryanodine receptors, and mitochondria. J Gen Physiol 116:547–560CrossRefGoogle Scholar
  94. 94.
    Suzuki A, Iwata J (2018) Molecular regulatory mechanism of exocytosis in the salivary glands. Int J Mol Sci 19.  https://doi.org/10.3390/ijms19103208 CrossRefGoogle Scholar
  95. 95.
    Tang B, Wu J, Zhu MX, Sun X, Liu J, Xie R, Dong TX, Xiao Y, Carethers JM, Yang S, Dong H (2019) VPAC1 couples with TRPV4 channel to promote calcium-dependent gastric cancer progression via a novel autocrine mechanism. Oncogene 38:3946–3961.  https://doi.org/10.1038/s41388-019-0709-6 CrossRefPubMedGoogle Scholar
  96. 96.
    Taylor CW (2017) Regulation of IP3 receptors by cyclic AMP. Cell Calcium 63:48–52.  https://doi.org/10.1016/j.ceca.2016.10.005 CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Taylor SE, Nguyen L, Halket C (1992) Carbachol potentiates isoprenaline-induced mucin secretion by rat submandibular gland. Naunyn Schmiedeberg's Arch Pharmacol 345:296–299.  https://doi.org/10.1007/bf00168690 CrossRefGoogle Scholar
  98. 98.
    Tornwall J, Uusitalo H, Hukkanen M, Sorsa T, Konttinen YT (1994) Distribution of vasoactive intestinal peptide (VIP) and its binding sites in labial salivary glands in Sjögren's syndrome and in normal controls. Clin Exp Rheumatol 12:287–292PubMedGoogle Scholar
  99. 99.
    Trebak M, Putney JW Jr (2017) ORAI calcium channels. Physiology (Bethesda) 32:332–342.  https://doi.org/10.1152/physiol.00011.2017 CrossRefGoogle Scholar
  100. 100.
    Tsuboi T, da Silva XG, Holz GG, Jouaville LS, Thomas AP, Rutter GA (2003) Glucagon-like peptide-1 mobilizes intracellular Ca2+ and stimulates mitochondrial ATP synthesis in pancreatic MIN6 beta-cells. Biochem J 369:287–299.  https://doi.org/10.1042/BJ20021288 CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Turner JT, Camden JM (1992) Regulation of secretion by vasoactive intestinal peptide in isolated perfused rat submandibular glands. Arch Oral Biol 37:281–287.  https://doi.org/10.1016/0003-9969(92)90050-i CrossRefPubMedGoogle Scholar
  102. 102.
    Tuvim MJ, Mospan AR, Burns KA, Chua M, Mohler PJ, Melicoff E, Adachi R, Ammar-Aouchiche Z, Davis CW, Dickey BF (2009) Synaptotagmin 2 couples mucin granule exocytosis to Ca2+ signaling from endoplasmic reticulum. J Biol Chem 284:9781–9787.  https://doi.org/10.1074/jbc.M807849200 CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Verkhratsky A (2005) Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons. Physiol Rev 85:201–279.  https://doi.org/10.1152/physrev.00004.2004 CrossRefPubMedGoogle Scholar
  104. 104.
    Wang CC, Shi H, Guo K, Ng CP, Li J, Gan BQ, Chien Liew H, Leinonen J, Rajaniemi H, Zhou ZH, Zeng Q, Hong W (2007) VAMP8/endobrevin as a general vesicular SNARE for regulated exocytosis of the exocrine system. Mol Biol Cell 18:1056–1063.  https://doi.org/10.1091/mbc.e06-10-0974 CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Watson GE, Latchney LR, Luo W, Hand AR, Culp DJ (1997) Biochemical and immunological studies and assay of rat sublingual mucins. Arch Oral Biol 42:161–172CrossRefGoogle Scholar
  106. 106.
    Wei W, Graeff R, Yue J (2014) Roles and mechanisms of the CD38/cyclic adenosine diphosphate ribose/Ca2+ signaling pathway. World J Biol Chem 5:58–67.  https://doi.org/10.4331/wjbc.v5.i1.58 CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Williams JA, Chen X, Sabbatini ME (2009) Small G proteins as key regulators of pancreatic digestive enzyme secretion. Am J Physiol Endocrinol Metab 296:E405–E414.  https://doi.org/10.1152/ajpendo.90874.2008 CrossRefPubMedGoogle Scholar
  108. 108.
    Wu CY, DiJulio DH, Jacobson KL, McKnight GS, Watson EL (2010) The contribution of AKAP5 in amylase secretion from mouse parotid acini. Am J Physiol (Cell Physiol) 298:C1151–C1158.  https://doi.org/10.1152/ajpcell.00382.2009 CrossRefGoogle Scholar
  109. 109.
    Yarotskyy V, Dirksen RT (2012) Temperature and RyR1 regulate the activation rate of store-operated Ca2+ entry current in myotubes. Biophys J 103:202–211.  https://doi.org/10.1016/j.bpj.2012.06.001 CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Yoshimura K, Fujita-Yoshigaki J, Murakami M, Segawa A (2002) Cyclic AMP has distinct effects from Ca2+ in evoking priming and fusion/exocytosis in parotid amylase secretion. Pflügers Arch 444:586–596.  https://doi.org/10.1007/s00424-002-0844-7 CrossRefPubMedGoogle Scholar
  111. 111.
    Zhang GH, Melvin JE (1993) Inhibitors of the intracellular Ca2+ release mechanism prevent muscarinic-induced Ca2+ influx in rat sublingual mucous acini. FEBS Lett 327:1–6.  https://doi.org/10.1016/0014-5793(93)81026-v CrossRefPubMedGoogle Scholar
  112. 112.
    Zhang GH, Melvin JE (1993) Membrane potential regulates Ca2+ uptake and inositol phosphate generation in rat sublingual mucous acini. Cell Calcium 14:551–562.  https://doi.org/10.1016/0143-4160(93)90076-i CrossRefPubMedGoogle Scholar
  113. 113.
    Zhang X, Wen J, Bidasee KR, Besch HR Jr, Rubin RP (1997) Ryanodine receptor expression is associated with intracellular Ca2+ release in rat parotid acinar cells. Am J Phys 273:C1306–C1314.  https://doi.org/10.1152/ajpcell.1997.273.4.C1306 CrossRefGoogle Scholar
  114. 114.
    Zhang F, Wan H, Yang X, He J, Lu C, Yang S, Tuo B, Dong H (2019) Molecular mechanisms of caffeine-mediated intestinal epithelial ion transports. Br J Pharmacol 176:1700–1716.  https://doi.org/10.1111/bph.14640 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Center for Oral BiologyUniversity of Rochester Medical CenterRochesterUSA
  2. 2.Department of Oral BiologyUF College of DentistryGainesvilleUSA
  3. 3.Unilever Research & Development, Port Sunlight LaboratoryBebingtonUK

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