Abstract
Secretions of the gastrointestinal (GI) tract were identified since antiquity. However, the role of these secretions in the process of digestion was not recognized after a couple of centuries. Modern knowledge about the secretory activity and regulation of the gut began with the work of Camillo Golgi (1843–1926), Jan Evangelista Purkyně (1787–1869), William Beaumont (1785–1853), Rudolph Heidenhain (1834–1897), Ivan Petrovich Pavlov (1849–1936). GI secretions include oral secretions (saliva), gastric juice, pancreatic juice, intestinal juice, bile, and other co-released components produced by the glandular cells of the digestive tract. Enzymes and their cofactors represent major components of these digestive juices that help to break down proteins, fats, and carbohydrates into simple absorbable substances. The GI juices also contain water, ions, mineral salts, and other endogenous proteins. In its broader sense, however, GI secretions include neuromediators and hormones. Of special attention is the secretion of the cells of the stomach (known as gastric juice), which has immense clinical implications in gastric pathology. Though it was widely accepted that hydrochloric acid is a major component of stomach juice, the clinical importance of gastric acid was not appreciated until the cellular and molecular mechanisms of gastric secretion were unraveled. It was known that gut secretions are controlled by a complex network involving the nervous and humoral systems as well as components of ingested food. However, nothing was known about the molecular processes regulating the secretory activity of the stomach. Compelling evidences on the mechanisms of regulation of gastric secretion came in the second half of the twentieth century following the groundbreaking investigations led by Sir James Whyte Black (1924–2010), which was rooted on chemical reception theory proposed around the beginning of the twentieth century by John Newport Langley (1852–1925) and Paul Ehrlich (1854–1915). The theory of chemical reception posits that chemical receptive substances (receptors), which are plasma membrane proteins, are required for receiving incoming chemical messengers (hormones and neurotransmitters) that initiate cellular response. The discovery of the hormone gastrin by John Sydney Edkins (1863–1940) in 1906 and of the GI source and functions of the hormone histamine by a student of Pavlov, Popielski Leon Bernardovich (Popielski Lev Bernardovich) (1866–1920) in 1916, coupled with the discovery of proton pumps in 1973 by Allen L. Ganser (1942–), and John Gaetano Forte (1934–2012), made it possible for the pioneer investigator Dr. George Sachs to extensively study proton pump inhibitors (PPI) and histamine (H) type 2 receptor blockers, which provided a good and superior alternative to gastric surgery that was initially the mainstay of treatment of gastric ulcer. This chapter not only gives a historic account on discoveries and the clinical importance of gastric secretions, but also discusses the mechanisms and secretory functions of the various regions of the GI tract.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- HCl:
-
Hydrochloric acid
- M1, M2, M3, M4, and M5:
-
Muscarinic acetylcholine receptor types
- µg/kg:
-
Microgram per kilogram
- µg/kg/h:
-
Microgram per kilogram per hour
- PPIs:
-
Proton pump inhibitors
- GABA:
-
Gamma-aminobutyric acid
- NO:
-
Nitric oxide
- CCK:
-
Cholecystokinin
- CNS:
-
Central nervous system
- 5-HT(2A):
-
Serotonin 2A (5-HT(2A)) receptor
- LD50 or LC50:
-
Lethal dose or concentration 50%
- nmol/kg:
-
Nanomole per kilogram
- microM:
-
Micromole
- 4-DAMP:
-
4-Diphenyl-acetoxy-N-methyl-piperidine
- ATP4A:
-
Adenosine triphosphate type 4A
- TM4, TM5, TM6, and TM8:
-
Transmembrane segments
- Kir4.1:
-
ATP-dependent inwardly rectifying potassium
- KCNQ1:
-
Voltage-gated potassium channel, KQT-like subfamily Q, member 1
- KCNE2:
-
Member 2 of the potassium voltage-gated channel subfamily E also known as MinK-related peptide 1 (MiRP1)
- CFTR:
-
Cystic fibrosis transmembrane conductance regulator
- CLIC-6:
-
Chloride intracellular channel protein 6
- Cl−:
-
Chloride ion
- K+:
-
Potassium ion
- KCC4:
-
K+-Cl− cotransporter type 4
- Å:
-
Armstrong
- GERD:
-
Gastroesophageal reflux disease
- SLC26A9:
-
Solute carrier family 26 (anion exchanger), member 9
Bibliography
Fry C (2009) Secretions of the salivary glands and stomach. Surgery (Oxford) 27(12):503–506
Hendrix TR, Paulk HT (1977) Intestinal secretion. Int Rev Physiol 12:257–284
Bhattarai Y, Schmidt BA, Linden DR, Larson ED, Grover M, Beyder A et al (2017) Human derived gut microbiota modulates colonic secretion in mice by regulating 5-HT3 receptor expression via acetate production. Am J Physiol Gastrointest Liver Physiol 313(1):G80–G87
Smolka AJ, Schubert ML (2017) Helicobacter pylori-induced changes in gastric acid secretion and upper gastrointestinal disease. In: Tegtmeyer N, Backert S (eds) Molecular pathogenesis and signal transduction by helicobacter pylori, volume 400 of the series current topics in microbiology and immunology. Springer International Publishing AG, Cham
Davison JS (1989) Gastrointestinal secretion. Wright Publishing Company, London
Camilleri M (2004) Chronic diarrhea: a review on pathophysiology and management for the clinical gastroenterologist. Clin Gastroenterol Hepatol 2(3):198–206
Kiela PR, Ghishan FK (2016) Physiology of intestinal absorption and secretion. Best Pract Res Clin Gastroenterol 30(2):145–159
Iorgulescu G (2009) Saliva between normal and pathological. Important factors in determining systemic and oral health. J Med Life 2(3):303–307
Kvietys PR, Granger DN (2010) Role of intestinal lymphatics in interstitial volume regulation and transmucosal water transport. Ann N Y Acad Sci 1207(1):E29–E43
Whitehead WE (1989) Effects of psychological factors on gastrointestinal function. In: Snape WJ Jr (ed) Pathogenesis of functional bowel disease, part of the series topics in gastroenterology. Springer, New York
Schneeman B (2004) Food factors and gastrointestinal function: a critical interface. BioFactors 21(1–4):85–88
Collado MC, Cernada M, Neu J, Pérez-Martínez G, Gormaz M, Vento M (2015) Factors influencing gastrointestinal tract and microbiota immune interaction in preterm infants. Pediatr Res 77:726–731
Park HW, Lee MG (2012) Transepithelial bicarbonate secretion: lessons from the pancreas. Cold Spring Harb Perspect Med 2(10):a009571
Glass GBJ (1964) Proteins, mucosubstances, and biologically active components of gastric secretion. Adv Clin Chem 7:235–372
Krogdahl Å, Sundby A, Bakke AM (2011) Integrated function and control of the gut. Gut secretion and digestion. In: Anthony FP (ed) Encyclopedia of fish physiology—from genome to environment. Elsevier, MA
Claustre J, Toumi F, Trompette A, Jourdan G, Guignard H, Chayvialle JA, Plaisancié P (2002) Effects of peptides derived from dietary proteins on mucus secretion in rat jejunum. Am J Physiol Gastrointest Liver Physiol 283(3):G521–G528
Feldman M (2013) American journal of gastroenterology lecture: gastric acid secretion: still relevant? Am J Gastroenterol 108:347–352
Kumar S, Hoh JH (2001) Probing the machinery of intracellular trafficking with the atomic force microscope. Traffic 2:746–756
Nickel W, Rabouille C (2009) Mechanisms of regulated unconventional protein secretion. Nat Rev Mol Cell Biol 10:148–155
Farhan H, Rabouille C (2011) Signalling to and from the secretory pathway. J Cell Sci 124:171–180
Baron S, Vangheluwe P, Sepúlveda MR, Wuytack F, Raeymaekers L, Vanoevelen J (2010) The secretory pathway Ca(2+)-ATPase 1 is associated with cholesterol-rich microdomains of human colon adenocarcinoma cells. Biochim Biophys Acta 1798(8):1512–1521
Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D, Darnell J (2000) Molecular cell biology, 4th edn. W. H. Freeman, New York
Abdullah LH, Davis CW (2007) Regulation of airway goblet cell mucin secretion by tyrosine phosphorylation signaling pathways. Am J Physiol Lung Cell Mol Physiol 293:L591–L599
Shifflett DE, Jones SL, Moeser AJ, Blikslager AT (2004) Mitogen-activated protein kinases regulate COX-2 and mucosal recovery in ischemic-injured porcine ileum. Am J Physiol Gastrointest Liver Physiol 286(6):G906–G913
Takeuchi Y, Yamada J, Yamada T, Todisco A (1997) Functional role of extracellular signal-regulated protein kinases in gastric acid secretion. Am J Physiol Gastrointest Liver Physiol 273(6):G1263–G1272
Logsdon CD, Ji B (2013) The role of protein synthesis and digestive enzymes in acinar cell injury. Nat Rev Gastroenterol Hepatol 10:362–370
Capoccia BJ, Jin RU, Kong YY, Peek RM Jr, Fassan M, Rugge M, Mills JC (2013) The ubiquitin ligase Mindbomb 1 coordinates gastrointestinal secretory cell maturation. J Clin Invest 123(4):1475–1491
Nakamoto T, Srivastava A, Romanenko VG, Ovitt CE, Perez-Cornejo P, Arreola J et al (2007) Functional and molecular characterization of the fluid secretion mechanism in human parotid acinar cells. Am J Physiol Regul Integr Comp Physiol 292(6):R2380–R2390
Nagasawa J (1977) Exocytosis: the common release mechanism of secretory granules in glandular cells, neurosecretory cells, neurons and paraneurons. Arch Histol Jpn 40:31–47
Nagasawa J, Douglas WW, Schulz RA (1970) Ultrastructural evidence of secretion by exocytosis and of “synaptic vesicle” formation in posterior pituitary glands. Nature 227(5256):407–409
Douglas WW, Nagasawa J, Schulz R (1971) Electron microscopic studies on the mechanism of secretion of posterior pituitary hormones and significance of microvesicles (“synaptic vesicles”): evidence of secretion by exocytosis and formation of microvesicles as a by-product of this process. Mem Soc Endocrinol 19:353–378
Halm DR, Halm ST (1999) Secretagogue response of goblet cells and columnar cells in human colonic crypts. Am J Physiol Cell Physiol 277(46):C501–C522
De Camilli P (1995) The eighth Datta lecture. Molecular mechanisms in synaptic vesicle recycling. FEBS Lett 369(1):3–12
Bonifacino JS, Glick BS (2004) The mechanisms of vesicle budding and fusion. Cell 116(2):153–166
Wu L-G, Hamid E, Shin W, Chiang H-C (2014) Exocytosis and endocytosis: modes, functions, and coupling mechanisms. Annu Rev Physiol 76:301–331
Matthews G (2002) Synaptic vesicle exocytosis: does a lingering kiss lead to fusion? Neuron 35(6):1013–1014
Galli T, Haucke V, Gough NR (2003) Synaptic vesicle fusion followed by clathrin-mediated endocytosis. Sci STKE 2003(198):tr3
Castle AM, Huang AY, Castle JD (2002) The minor regulated pathway, a rapid component of salivary secretion, may provide docking/fusion sites for granule exocytosis at the apical surface of acinar cells. J Cell Sci 115:2963–2973
Koo SJ, Kochlamazashvili G, Rost B, Puchkov D, Gimber N, Lehmann M et al (2015) Vesicular synaptobrevin/VAMP2 levels guarded by AP180 control efficient neurotransmission. Neuron 88(2):330–344
Rajappa R, Gauthier-Kemper A, Böning D, Hüve J, Klingauf J (2016) Synaptophysin 1 clears synaptobrevin 2 from the presynaptic active zone to prevent short-term depression. Cell Rep 14(6):1369–1381
Tsuboi T, McMahon HT, Rutter GA (2004) Mechanisms of dense core vesicle recapture following “kiss and run” (“cavicapture”) exocytosis in insulin-secreting cells. J Biol Chem 279:47115–47124
Oishi Y, Arakawa T, Tanimura A, Itakura M, Takahashi M, Tajima Y et al (2006) Role of VAMP-2, VAMP-7, and VAMP-8 in constitutive exocytosis from HSY cells. Histochem Cell Biol 125(3):273–281
Wang C-C, Shi H, Guo K, Ng CP, Li J, Gan BQ et al (2007) VAMP8/endobrevin as a general vesicular SNARE for regulated exocytosis of the exocrine system. Mol Biol Cell 18(3):1056–1063
Barrera MJ, Sánchez M, Aguilera S, Alliende C, Bahamondes V, Molina C et al (2012) Aberrant localization of fusion receptors involved in regulated exocytosis in salivary glands of Sjögren’s syndrome patients is linked to ectopic mucin secretion. J Autoimmun 39(1–2):83–92
Gaffield MA, Betz WJ (2007) Imaging synaptic vesicle exocytosis and endocytosis with FM dyes. Nat Protocols 1:2916–2921
Tsuboi T (2008) Molecular mechanism of docking of dense-core vesicles to the plasma membrane in neuroendocrine cells. Med Mol Morphol 41:68
Gong LW, Hafez I, Alvarez de Toledo G, Lindau M (2003) Secretory vesicles membrane area is regulated in tandem with quantal size in chromaffin cells. J Neurosci 23(21):7917–7921
Edgar WM (1992) Saliva: its secretion, composition and functions. Br Dent J 172(8):305–312
du Toit DF, Nortjé C (2004) Salivary glands: applied anatomy and clinical correlates. SADJ 59(2):65–66, 69–71, 73–74
Ellis H (2012) Anatomy of the salivary glands. Surgery 30(11):569–572
Humphrey SP, Williamson RT (2001) A review of saliva: normal composition, flow, and function. J Prosthet Dent 85(2):162–169
Ferguson DB (1999) The flow rate and composition of human labial gland saliva. Arch Oral Biol 44(1):S11–S14
Sonesson M (2011) On minor salivary gland secretion in children, adolescents and adults. Swed Dent J 215:9–64
Sonesson M, Ericson D, Kinnby B, Wickström C (2011) Glycoprotein 340 and sialic acid in minor-gland and whole saliva of children, adolescents, and adults. Eur J Oral Sci 119(6):435–440
Varga G (2012) Physiology of the salivary glands. Surgery (Oxford) 30(11):578–583
Lee MG, Ohana E, Park HW, Yang D, Muallem S (2012) Molecular mechanism of pancreatic and salivary gland fluid and HCO3− secretion. Physiol Rev 92(1):39–74
Amano O, Mizobe K, Bando Y, Sakiyama K (2012) Anatomy and histology of rodent and human major salivary glands. Acta Histochem Cytochem 45(5):241–250
Hunter KD, Wilson WS (1995) The effects of antidepressant drugs on salivary flow and content of sodium and potassium ions in human parotid saliva. Arch Oral Biol 40:983–989
Silvers AR, Som PM (1998) Salivary glands. Radiol Clin North Am 36(5):941–966
Nadershah M, Salama A (2012) Removal of parotid, submandibular, and sublingual glands. Oral Maxillofac Surg Clin North Am 24(2):295–305
Lakraj AA, Moghimi N, Jabbari B (2013) Sialorrhea: anatomy, pathophysiology and treatment with emphasis on the role of botulinum toxins. Toxins (Basel) 5(5):1010–1031
Leung AKC, Kao CP (1999) Drooling in children. Paediatr Child Health 4(6):406–411
Zlotnik Y, Balash Y, Korczyn AD, Giladi N, Gurevich T (2015) Disorders of the oral cavity in parkinson’s disease and parkinsonian syndromes. Parkinsons Dis 2015:379482
Restivo DA, Panebianco M, Casabona A, Lanza S, Marchese-Ragona R, Patti F, et al (2018) Botulinum toxin A for sialorrhoea associated with neurological disorders: evaluation of the relationship between effect of treatment and the number of glands treated. Toxins (Basel) 10(2):E55
Dashtipour K, Bhidayasiri R, Chen JJ, Jabbari B, Lew M, Torres-Russotto D (2017) RimabotulinumtoxinB in sialorrhea: systematic review of clinical trials. J Clin Mov Disord 4:9
Petracca M, Guidubaldi A, Ricciardi L, Ialongo T, Del Grande A, Mulas D, et al (2015) Botulinum toxin A and B in sialorrhea: long-term data and literature overview. Toxicon 107(Pt A):129–140
Kondo Y, Nakamoto T, Jaramillo Y, Choi S, Catalan MA, Melvin JE (2015) Functional differences in the acinar cells of the murine major salivary glands. J Dent Res 94(5):715–721
Delporte C, Bryla A, Perret J (2016) Aquaporins in salivary glands: from basic research to clinical applications. Int J Mol Sci 17(2):166
Holmberg KV, Hoffman MP (2014) Anatomy, biogenesis, and regeneration of salivary glands. Monogr Oral Sci 24:1–13
Shah AAK, Mulla AF, Mayank M (2016) Pathophysiology of myoepithelial cells in salivary glands. J Oral Maxillofac Pathol 20(3):480–490
Balachander N, Masthan KMK, Babu NA, Anbazhagan V (2015) Myoepithelial cells in pathology. J Pharm Bioallied Sci 7(1):S190–S193
Patterson K, Catalán MA, Melvin JE, Yule DI, Crampin EJ, Sneyd J (2012) A quantitative analysis of electrolyte exchange in the salivary duct. Am J Physiol Gastrointest Liver Physiol 303(10):G1153–G1163
Sato A (2007) Tuft cells. Anat Sci Int 82(4):187–199
Sato A, Miyoshi S (1996) Tuft cells in the main excretory duct epithelia of the three major rat salivary glands. Eur J Morphol 34(3):225–228
Segawa A, Loffredo F, Puxeddu R, Yamashina S, Testa Riva F, Riva A (1998) Exocytosis in human salivary glands visualized by high-resolution scanning electron microscopy. Cell Tissue Res 291(2):325–336
Hand AR, Pathmanathan D, Field RB (1999) Morphological features of the minor salivary glands. Arch Oral Biol 44(1):S3–S10
Stephens LC, King GK, Peters LJ, Ang KK, Schultheiss TE, Jardine JH (1986) Unique radiosensitivity of serous cells in rhesus monkey submandibular glands. Am J Pathol 124(3):479–487
Davis PB (1987) Pathophysiology of cystic fibrosis with emphasis on salivary gland involvement. J Dent Res 66:667–671
Lydiatt DD, Bucher GS (2012) The historical evolution of the understanding of the submandibular and sublingual salivary glands. Clin Anat 25(1):2–11
Trivedi N (2015) Tumors of the parotid. Atlas of head and neck cancer surgery. Springer, New Delhi
Larian B (2016) Parotidectomy for benign parotid tumors. Otolaryngol Clin N Am 49:395–413
Carlson GW (2000) The salivary glands. Embryology, anatomy, and surgical applications. Surg Clin North Am 80(1):261–273, xii
Kuijper-Lenstra AH, Kramer MF (1975) Rate of protein synthesis in rat salivary gland cells after pilocarpine or feeding. I. Rate of (glyco) protein secretion from cells of mixed salivary glands. Cell Tissue Res 164(4):435–446
Ohshima H (2014) Dental and oral biology, anatomy. In: Caplan M, Bradshaw RA, Bylund DB, Carlson BM, Enna SJ, Hart GW et al (eds) Physiology of the digestive system. Human physiology. Reference module in biomedical sciences. Elsevier, MA
Rastogi R, Bhargava S, Mallarajapatna GJ, Singh SK (2012) Pictorial essay: salivary gland imaging. Indian J Radiol Imaging 22(4):325–333
Ekström J, Khosravani N, Castagnola M, Messana I (2011) Saliva and the control of its secretion. In: Ekberg O (ed) Dysphagia. Medical radiology. Springer, Heidelberg
Tandler B, Pinkstaff CA, Riva A (1994) Ultrastructure and histochemistry of human anterior lingual salivary glands (glands of Blandin and Nuhn). Anat Rec 240(2):167–177
Cheng SJ, Huang CF, Chen YC, Lee JJ, Chang HH, Chen HM et al (2009) Ultrastructural changes of posterior lingual glands after hypoglossal denervation in hamsters. J Anat 214(1):163–170
Riva A, Puxeddu R, Uras L, Loy F, Serreli S, Testa Riva F (2000) A high resolution sem study of human minor salivary glands. Eur J Morphol 38(4):219–226
Kraitrakul S, Sirithunyaporn S, Yimtae K (2001) Distribution of minor salivary glands in the peritonsillar space. J Med Assoc Thai 84(3):371–378
Kumaresan R, Karthikeyan P, Mohammed F, Fairozekhan AT (2013) A novel technique for the management of Blandin-Nuhn mucocele: a case report. Int J Clin Pediatr Dent 6(3):201–204
Leon NG, Pardo GEM (2013) Mucocele of the glands of Blandin-Nuhn: a case report. Colomb Med (Cali) 44(1):46–47
Siqueira WL, Salih E, Wan DL, Helmerhorst EJ, Oppenheim FG (2008) Proteome of human minor salivary gland secretion. J Dent Res 87(5):445–450
Perez P, Rowzee AM, Zheng C, Adriaansen J, Baum BJ (2010) Salivary epithelial cells: an unassuming target site for gene therapeutics. Int J Biochem Cell Biol 42(6):773–777
Lantini MS, Proto E, Puxeddu P, Riva A, Testa Riva F (1990) Fine structure of excretory ducts of human salivary glands. J Submicrosc Cytol Pathol 22(3):465–475
Chitturi RT, Veeravarmal V, Nirmal RM, Reddy BVR (2015) Myoepithelial cells (MEC) of the salivary glands in health and tumours. J Clin Diagn Res 9(3):ZE14–ZE18
Ianez RF, Buim ME, Coutinho-Camillo CM, Schultz R, Soares FA, Lourenço SV (2010) Human salivary gland morphogenesis: myoepithelial cell maturation assessed by immunohistochemical markers. Histopathology 57(3):410–417
Nakamoto T, Romanenko V, Melvin JE (2007) The electrolyte and water secretion mechanism. J Oral Biosci 49(1):27–30
Cutler LS, Gremski W (1991) Epithelial-mesenchymal interactions in the development of salivary glands. Crit Rev Oral Biol Med 2(1):1–12
Chan YH, Huang TW, Young TH, Lou PJ (2011) Human salivary gland acinar cells spontaneously form three-dimensional structures and change the protein expression patterns. J Cell Physiol 226(11):3076–3085
Logsdon CD, Ji B (2013) The role of protein synthesis and digestive enzymes in acinar cell injury. Nat Rev Gastroenterol Hepatol 10(6):362–370
Turner JR, Sugiya H (2002) Understanding salivary fluid and protein secretion. Oral Dis 8:3–11
Kim SK, Cuzzort LM, McKean RK (1992) Amylase mRNA synthesis and ageing in rat parotid glands following isoproterenol-stimulated secretion. Arch Oral Biol 37(5):349–354
Horii A, Emi M, Tomita N, Nishide T, Ogawa M, Mori T, Matsubara K (1987) Primary structure of human pancreatic alpha-amylase gene: its comparison with human salivary alpha-amylase gene. Gene 60(1):57–64
Bonnefond A, Yengo L, Dechaume A, Canouil M, Castelain M, Roger E et al (2017) Relationship between salivary/pancreatic amylase and body mass index: a systems biology approach. BMC Med 15(1):37
Falchi M, El-Sayed Moustafa JS, Takousis P, Pesce F, Bonnefond A, Andersson-Assarsson JC et al (2014) Low copy number of the salivary amylase gene predisposes to obesity. Nat Genet 46:492–497
Castle D, Castle A (1998) Intracellular transport and secretion of salivary proteins. Crit Rev Oral Biol Med 9(l):4–22
Yokouchi H, Horii A, Emi M, Tomita N, Doi S, Ogawa M et al (1990) Cloning and characterization of a third type of human alpha-amylase gene, AMY2B. Gene 90(2):281–286
Samuelson LC, Wiebauer K, Gumucio DL, Meisler MH (1988) Expression of the human amylase genes: recent origin of a salivary amylase promoter from an actin pseudogene. Nucleic Acids Res 16(17):8261–8276
Carpenter D, Dhar S, Mitchell LM, Fu B, Tyson J, Shwan NA et al (2015) Obesity, starch digestion and amylase: association between copy number variants at human salivary (AMY1) and pancreatic (AMY2) amylase genes. Hum Mol Genet 24(12):3472–3480
Fábián TK, Hermann P, Beck A, Fejérdy P, Fábián G (2012) Salivary defense proteins: their network and role in innate and acquired oral immunity. Int J Mol Sci 13(4):4295–4320
Murakami M, Ohtake T, Dorschner RA, Gallo RL (2002) Cathelicidin antimicrobial peptides are expressed in salivary glands and saliva. J Dent Res 81(12):845–850
Storesund T, Schreurs O, Messelt EB, Kolltveit KM, Schenck K (2009) Trefoil factor family 3 expression in the oral cavity. Eur J Oral Sci 117(6):636–643
Jagla W, Wiede A, Hinz M, Dietzmann K, Gülicher D, Gerlach KL, Hoffmann W (1999) Secretion of TFF-peptides by human salivary glands. Cell Tissue Res 298(1):161–166
Taichman NS, Cruchley AT, Fletcher LM, Hagi-Pavli EP, Paleolog EM, Abrams WR et al (1998) Vascular endothelial growth factor in normal human salivary glands and saliva: a possible role in the maintenance of mucosal homeostasis. Lab Invest 78(7):869–875
Leclair EE (2003) Four BPI (bactericidal/permeability-increasing protein)-like genes expressed in the mouse nasal, oral, airway and digestive epithelia. Biochem Soc Trans 31(Pt 4):801–805
Wheeler TT, Haigh BJ, McCracken JY, Wilkins RJ, Morris CA, Grigor MR (2002) The BSP30 salivary proteins from cattle, LUNX/PLUNC and von Ebner’s minor salivary gland protein are members of the PSP/LBP superfamily of proteins. Biochim Biophys Acta 1579(2–3):92–100
Wheeler TT, Hood KA, Maqbool NJ, McEwan JC, Bingle CD, Zhao S (2007) Expansion of the bactericidal/permeability increasing-like (BPI-like) protein locus in cattle. BMC Genom 8:75
Petersen OH, Tepikin AV (2008) Polarized calcium signaling in exocrine gland cells. Annu Rev Physiol 70:273–299
Salido GM, Sage SO, Rosado JA (2009) Biochemical and functional properties of the store-operated Ca2+ channels. Cell Signal 21(4):457–461
Chen KT, Ong HL, Liu X, Ambudkar IS (2011) Contribution of TRPC1 and Orai1 to Ca2+ entry activated by store depletion. Adv Exp Med Biol 704:435–449
Froehlich DA, Pangborn RM, Whitaker JR (1987) The effect of oral stimulation on human parotid salivary flow rate and alpha-amylase secretion. Physiol Behav 41(3):209–217
Williams JA (1981) Electrical correlates of secretion in endocrine and exocrine cells. Fed Proc 40(2):128–134
Park HS, Betzenhauser MJ, Zhang Y, Yule DI (2012) Regulation of Ca2+ release through inositol 1,4,5-trisphosphate receptors by adenine nucleotides in parotid acinar cells. Am J Physiol Gastrointest Liver Physiol 302(1):G97–G104
Benes C, Soltoff SP (2001) Modulation of PKCδ tyrosine phosphorylation and activity in salivary and PC-12 cells by Src kinases. Am J Physiol Cell Physiol 280(6):C1498–C1510
Ishikawa Y, Ishida H (2000) Aquaporin water channel in salivary glands. Jpn J Pharmacol 83(2):95–101
Putney JW Jr (1982) Inositol lipids and cell stimulation in mammalian salivary gland. Cell Calcium 3(4–5):369–383
Turner JT, Landon LA, Gibbons SJ, Talamo BR (1999) Salivary gland P2 nucleotide receptors. Crit Rev Oral Biol Med 10(2):210–224
Nauntofte B (1992) Regulation of electrolyte and fluid secretion in salivary acinar cells. Am J Physiol 263(6 Pt 1):G823–G837
Kim J-H, Park S-H, Moon YW, Hwang S, Kim D, Jo S-H et al (2009) Histamine H1 receptor induces cytosolic calcium increase and aquaporin translocation in human salivary gland cells. J Pharmacol Exp Ther 330(2):403–412
Ambudkar IS (2014) Ca2+ signaling and regulation of fluid secretion in salivary gland acinar cells. Cell Calcium 55(6):297–305
Beroukas D, Goodfellow R, Hiscock J, Jonsson R, Gordon TP, Waterman SA (2002) Up-regulation of M3-muscarinic receptors in labial salivary gland acini in primary Sjögren’s syndrome. Lab Invest 82:203–210
Kajiya M, Ichimonji I, Min C, Zhu T, Jin J-O, Yu Q et al (2012) Muscarinic type 3 receptor induces cytoprotective signaling in salivary gland cells through epidermal growth factor receptor transactivation. Mol Pharmacol 82(1):115–124
Melvin JE, Yule D, Shuttleworth T, Begenisich T (2005) Regulation of fluid and electrolyte secretion in salivary gland acinar cells. Annu Rev Physiol 67:445–469
Maruyama Y, Gallacher DV, Petersen OH (1983) Voltage and Ca2+-activated K+ channel in baso-lateral acinar cell membranes of mammalian salivary glands. Nature 302(5911):827–829
Catalán MA, Peña-Munzenmayer G, Melvin JE (2014) Ca2+-dependent K+ channels in exocrine salivary glands. Cell Calcium 55(6):362–368
Ishikawa T, Murakami M, Seo Y (1994) Basolateral K+ efflux is largely independent of maxi-K+ channels in rat submandibular glands during secretion. Pflugers Arch 428(5–6):516–525
Morris AP, Gallacher DV, Fuller CM, Scott J (1987) Cholinergic receptor-regulation of potassium channels and potassium transport in human submandibular acinar cells. J Dent Res 66(2):541–546
Frizzell RA, Hanrahan JW (2012) Physiology of epithelial chloride and fluid secretion. Cold Spring Harb Perspect Med 2(6):a009563
Melvin JE (1999) Chloride channels and salivary gland function. Crit Rev Oral Biol Med 10(2):199–209
Yang D, Shcheynikov N, Zeng W, Ohana E, So I, Ando H et al (2009) IRBIT coordinates epithelial fluid and HCO3− secretion by stimulating the transporters pNBC1 and CFTR in the murine pancreatic duct. J Clin Invest 119(1):193–202
Ando H, Kawaai K, Mikoshiba K (2014) IRBIT: a regulator of ion channels and ion transporters. Biochim Biophys Acta 1843(10):2195–2204
Yamaguchi S, Ishikawa T (2008) The electrogenic Na+-HCO3− cotransporter NBCe1-B is regulated by intracellular Mg2+. Biochem Biophys Res Commun 376(1):100–104
Lee S-K, Boron WF, Parker MD (2012) Relief of autoinhibition of the electrogenic Na-HCO3 cotransporter NBCe1-B: role of IRBIT vs. amino-terminal truncation. Am J Physiol Cell Physiol 302(3):C518–C526
Jalali R, Guo J, Zandieh-Doulabi B, Bervoets TJM, Paine ML, Boron WF et al (2014) NBCe1 (SLC4A4) a potential pH regulator in enamel organ cells during enamel development in the mouse. Cell Tissue Res 358(2):433–442
Ando H, Kawaai K, Mikoshiba K (2014) IRBIT: a regulator of ion channels and ion transporters. Biochim Biophys Acta Mol Cell Res 1843(10):2195–2204
Castle D, Castle A (1998) Intracellular transport and secretion of salivary proteins. Crit Rev Oral Biol Med 9(1):4–22
Castle JD, Castle AM (1993) Sorting and secretion of salivary proteins. Crit Rev Oral Biol Med 4(3–4):393–398
Castle JD (1990) Sorting and secretory pathways in exocrine cells. Am J Respir Cell Mol Biol 2(2):119–126
Venkatesh SG, Tan J, Gorr SU, Darling DS (2007) Isoproterenol increases sorting of parotid gland cargo proteins to the basolateral pathway. Am J Physiol Cell Physiol 293(2):C558–C565
Fujita-Yoshigaki J, Matsuki-Fukushima M, Yokoyama M, Katsumata-Kato O (2013) Sorting of a HaloTag protein that has only a signal peptide sequence into exocrine secretory granules without protein aggregation. Am J Physiol Gastrointest Liver Physiol 305(10):G685–G696
von Zastrow M, Castle JD (1987) Protein sorting among two distinct export pathways occurs from the content of maturing exocrine storage granules. J Cell Biol 105(6 Pt 1):2675–2684
Carlo AS, Nykjaer A, Willnow TE (2014) Sorting receptor sortilin-a culprit in cardiovascular and neurological diseases. J Mol Med (Berl). 92(9):905–911
Padilla BE, Cottrell GS, Roosterman D, Pikios S, Muller L, Steinhoff M, Bunnett NW (2007) Endothelin-converting enzyme-1 regulates endosomal sorting of calcitonin receptor-like receptor and beta-arrestins. J Cell Biol 179(5):981–997
Katzmann DJ, Odorizzi G, Emr SD (2002) Receptor downregulation and multivesicular-body sorting. Nat Rev Mol Cell Biol 3:893–905
Chapman RE (1994) Vacuolar sorting: tracking down an elusive receptor. Curr Biol 4(11):1019–1022
Varga G (2015) Physiology of the salivary glands. Surgery 33(12):581–586
Cannon RM, Lee CE (2013) Salivary gland physiology. In: Kountakis SE (ed) Encyclopedia of otolaryngology, head and neck surgery. Springer, Heidelberg
Hand AR (1990) The secretory process of salivary glands and pancreas. In: Riva A, Motta PM, Riva FT (eds) Ultrastructure of the extraparietal glands of the digestive tract. Springer, New York
Huang AY, Castle AM, Hinton BT, Castle JD (2001) Resting (basal) secretion of proteins is provided by the minor regulated and constitutive-like pathways and not granule exocytosis in parotid acinar cells. J Biol Chem 276(25):22296–22306
Wang J, Cawley NX, Voutetakis A, Rodriguez YM, Goldsmith CM, Nieman LK et al (2005) Partial redirection of transgenic human growth hormone secretion from rat salivary glands. Hum Gene Ther 16(5):571–583
Proctor GB (2016) The physiology of salivary secretion. Periodontol 2000 70(1):11–25
Okuma N, Saita M, Hoshi N, Soga T, Tomita M, Sugimoto M, Kimoto K (2017) Effect of masticatory stimulation on the quantity and quality of saliva and the salivary metabolomic profile. PLoS ONE 12(8):e0183109
Marquezin MC, Pedroni-Pereira A, Araujo DS, Rosar JV, Barbosa TS, Castelo PM (2016) Descriptive analysis of the masticatory and salivary functions and gustatory sensitivity in healthy children. Acta Odontol Scand 74(6):443–448
Catalán MA, Nakamoto T, Melvin JE (2009) The salivary gland fluid secretion mechanism. J Med Invest 56:192–196
Martinez JR (1987) Ion transport and water movement. J Dent Res 66:638–647
Thaysen JH, Thorn NA, Schwartz IL (1954) Excretion of sodium, potassium, chloride and carbon dioxide in human parotid saliva. Am J Physiol 178(1):155–159
Roussa E (2011) Channels and transporters in salivary glands. Cell Tissue Res 343(2):263–287
Ohana E (2015) Transepithelial ion transport across duct cells of the salivary gland. Oral Dis 21(7):826–835
Baker OJ (2016) Current trends in salivary gland tight junctions. Tissue Barriers 4(3):e1162348
Alam J, Choi YS, Koh JH, Kwok S-K, Park S-H, Song YW et al (2017) Detection of autoantibodies against aquaporin-1 in the sera of patients with primary Sjögren’s syndrome. Immune Netw 17(2):103–109
Delporte C (2014) Aquaporins in salivary glands and pancreas. Biochim Biophys Acta 1840(5):1524–1532
Delporte C, Steinfeld S (2006) Distribution and roles of aquaporins in salivary glands. Biochim Biophys Acta 1758(8):1061–1070
Gresz V, Kwon TH, Hurley PT, Varga G, Zelles T, Nielsen S et al (2001) Identification and localization of aquaporin water channels in human salivary glands. Am J Physiol Gastrointest Liver Physiol 281(1):G247–G254
Proctor GB, Carpenter GH (2007) Regulation of salivary gland function by autonomic nerves. Auton Neurosci 133(1):3–18
Lai Z, Yin H, Cabrera-Pérez J, Guimaro MC, Afione S, Michael DG et al (2016) Aquaporin gene therapy corrects Sjögren’s syndrome phenotype in mice. Proc Natl Acad Sci U S A 113(20):5694–5699
Carpenter GH (2013) The secretion, components, and properties of saliva. Annu Rev Food Sci Technol 4:267–276
Thie NM, Kato T, Bader G, Montplaisir JY, Lavigne GJ (2002) The significance of saliva during sleep and the relevance of oromotor movements. Sleep Med Rev 6(3):213–227
Esser D, Alvarez-Llamas G, de Vries MP, Weening D, Vonk RJ, Roelofsen H (2008) Sample stability and protein composition of saliva: implications for its use as a diagnostic fluid. Biomark Insights 3:25–27
de Almeida Pdel V, Grégio AM, Machado MA, de Lima AA, Azevedo LR (2008) Saliva composition and functions: a comprehensive review. J Contemp Dent Pract 9(3):72–80
Damle SG, Vidya I, Yadav R, Bhattal H, Loomba A (2012) Quantitative determination of inorganic constituents in saliva and their relationship with dental caries experience in children. Dentistry 2:131
Isenman L, Liebow C, Rothman S (1999) The endocrine secretion of mammalian digestive enzymes by exocrine glands. Am J Physiol Endocrinol Metab 276(2):E223–E232
Zolotukhin S (2013) Metabolic hormones in saliva: origins and functions. Oral Dis 19(3):219–229
Tiwari M (2011) Science behind human saliva. J Nat Sci Biol Med 2(1):53–58
Granger DA, Shirtcliff EA, Booth A, Kivlighan KT, Schwartz EB (2004) The “trouble” with salivary testosterone. Psychoneuroendocrinology 29(10):1229–1240
Mathison RD, Davison JS, Befus AD, Gingerich DA (2010) Salivary gland derived peptides as a new class of anti-inflammatory agents: review of preclinical pharmacology of C-terminal peptides of SMR1 protein. J Inflamm 7:49
Leonora J, Tieche J-M, Celestin J (1987) Physiological factors affecting secretion of parotid hormone. Am J Physiol 252(4 Pt 1):E477–E484
Gröschl M (2009) The physiological role of hormones in saliva. BioEssays 31(8):843–852
Lindell SG, Suomi SJ, Shoaf S, Higley JD, Linnoila M (1999) Salivary prolactin as a marker for central serotonin turnover. Biol Psychiatry 46(4):568–572
Kanno T, Asada N, Yanase H, Iwanaga T, Ozaki T, Nishikawa Y et al (1999) Salivary secretion of highly concentrated chromogranin a in response to noradrenaline and acetylcholine in isolated and perfused rat submandibular glands. Exp Physiol 84(6):1073–1083
Gröschl M, Topf HG, Kratzsch J, Dötsch J, Rascher W, Rauh M (2005) Salivary leptin induces increased expression of growth factors in oral keratinocytes. J Mol Endocrinol 34(2):353–366
Gröschl M, Topf HG, Bohlender J, Zenk J, Klussmann S, Dötsch J et al (2005) Identification of ghrelin in human saliva: production by the salivary glands and potential role in proliferation of oral keratinocytes. Clin Chem 51(6):997–1006
Gröschl M, Wendler O, Topf HG, Bohlender J, Köhler H (2009) Significance of salivary adrenomedullin in the maintenance of oral health: stimulation of oral cell proliferation and antibacterial properties. Regul Pept 154(1–3):16–22
Šimo L, Koči J, Žitňan D, Park Y (2011) Evidence for D1 dopamine receptor activation by a paracrine signal of dopamine in tick salivary glands. PLoS ONE 6(1):e16158
Sabbadini E, Berczi I (1995) The submandibular gland: a key organ in the neuro-immuno-regulatory network? NeuroImmunoModulation 2(4):184–202
Nederfors T, Dahlöf C (1996) Effects on salivary flow rate and composition of withdrawal of and re-exposure to the beta 1-selective antagonist metoprolol in a hypertensive patient population. Eur J Oral Sci 104(3):262–268
Arhakis A, Karagiannis V, Kalfas S (2013) Salivary alpha-amylase activity and salivary flow rate in young adults. Open Dent J 7:7–15
Gorr S-U, Venkatesh SG, Darling DS (2005) Parotid secretory granules: crossroads of secretory pathways and protein storage. J Dent Res 84(6):500–509
Messenger SW, Falkowski MA, Groblewski GE (2014) Ca2+-regulated secretory granule exocytosis in pancreatic and parotid acinar cells. Cell Calcium 55(6):369–375
Cosen-Binker LI, Gaisano HY (2007) Recent insights into the cellular mechanisms of acute pancreatitis. Can J Gastroenterol 21(1):19–24
Leonora J, Tieche JM, Steinman RR (1993) Further evidence for a hypothalamus-parotid gland endocrine axis in the rat. Arch Oral Biol 38(10):911–916
Leonora J, Tieche JM, Celestin J (1987) Physiological factors affecting secretion of parotid hormone. Am J Physiol Endocrinol Metab 252(4):E477–E484
Anderson LC (1998) Hormonal regulation of salivary glands, with particular reference to experimental diabetes. Front Oral Biol 10:200–221
Yagi T, Ueda H, Amitani H, Asakawa A, Miyawaki S, Inui A (2012) The role of ghrelin, salivary secretions, and dental care in eating disorders. Nutrients 4(8):967–989
Nigro E, Piombino P, Scudiero O, Monaco ML, Schettino P, Chambery A, Daniele A (2015) Evaluation of salivary adiponectin profile in obese patients. Peptides 63:150–155
Rabe K, Lehrke M, Parhofer KG, Broedl UC (2008) Adipokines and insulin resistance. Mol Med 14(11–12):741–751
Mamali I, Roupas ND, Armeni AK, Theodoropoulou A, Markou KB, Georgopoulos NA (2012) Measurement of salivary resistin, visfatin and adiponectin levels. Peptides 33(1):120–124
Antuna-Puente B, Feve B, Fellahi S, Bastard JP (2008) Adipokines: the missing link between insulin resistance and obesity. Diabetes Metab 34(1):2–11
Cantarini L, Obici L, Simonini G, Cimaz R, Bacarelli MR, Merlini G et al (2012) Serum leptin, resistin, visfatin and adiponectin levels in tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Clin Exp Rheumatol 30(3 Suppl 72):S108–S114
Tabari ZA, Ghaedi FB, Azadmehr A, Nohekhan A, Tabrizi MAA, Ardakani MRT et al (2015) . Salivary visfatin concentration in response to non-surgical periodontal therapy. J Clin Diagn Res 9:ZC05–ZC08
Özcan E, Saygun NI, Serdar MA, Kurt N (2015) Evaluation of the salivary levels of visfatin, chemerin, and progranulin in periodontal inflammation. Clin Oral Invest 19(4):921–928
Rao PV, Reddy AP, Lu X, Dasari S, Krishnaprasad A, Biggs E et al (2009) Proteomic identification of salivary biomarkers of type-2 diabetes. J Proteome Res 8(1):239–245
Loo JA, Yan W, Ramachandran P, Wong DT (2010) comparative human salivary and plasma proteomes. J Dent Res 89(10):1016–1023
Thomsson KA, Prakobphol A, Leffler H, Reddy MS, Levine MJ, Fisher SJ, Hansson GC (2002) The salivary mucin MG1 (MUC5B) carries a repertoire of unique oligosaccharides that is large and diverse. Glycobiology 12(1):1–14
Zalewska A, Zwierz K, Zółkowski K, Gindzieński A (2000) Structure and biosynthesis of human salivary mucins. Acta Biochim Pol 47(4):1067–1079
Mehrotra R, Thornton DJ, Sheehan JK (1998) Isolation and physical characterization of the MUC7 (MG2) mucin from saliva: evidence for self-association. Biochem J 334(Pt 2):415–422
Liu B, Rayment SA, Gyurko C, Oppenheim FG, Offner GD, Troxler RF (2000) The recombinant N-terminal region of human salivary mucin MG2 (MUC7) contains a binding domain for oral Streptococci and exhibits candidacidal activity. Biochem J 345(3):557–564
Liu B, Rayment S, Oppenheim FG, Troxler RF (1999) Isolation of human salivary mucin MG2 by a novel method and characterization of its interactions with oral bacteria. Arch Biochem Biophys 364(2):286–293
Park W-K, Chung J-W, Kim Y-K, Chung S-C, Kho H-S (2006) Influences of animal mucins on lysozyme activity in solution and on hydroxyapatite surfaces. Arch Oral Biol 51(10):861–869
Loomis RE, Prakobphol A, Levine MJ, Reddy MS, Jones PC (1987) Biochemical and biophysical comparison of two mucins from human submandibular-sublingual saliva. Arch Biochem Biophys 258(2):452–464
Fábián TK, Fejérdy P, Nguyen MT, Sőti C, Csermely P (2007) Potential immunological functions of salivary Hsp70 in mucosal and periodontal defense mechanisms. Arch Immunol Ther Exp 55:1–8
Soares RV, Siqueira CC, Bruno LS, Oppenheim FG, Offner GD, Troxler RF (2003) MG2 and lactoferrin form a heterotypic complex in salivary secretions. J Dent Res 82(6):471–475
de Sousa-Pereira P, Amado F, Abrantes J, Ferreira R, Esteves PJ, Vitorino R (2013) An evolutionary perspective of mammal salivary peptide families: cystatins, histatins, statherin and PRPs. Arch Oral Biol 58(5):451–458
Schlesinger DH, Hay DI, Levine MJ (1989) Complete primary structure of statherin, a potent inhibitor of calcium phosphate precipitation, from the saliva of the monkey, macaca arctoides. Int J Pept Protein Res 34(5):374–380
Schlesinger DH, Hay DI (1977) Complete covalent structure of statherin, a tyrosine-rich acidic peptide which inhibits calcium phosphate precipitation from human parotid saliva. J Biol Chem 252:1689–1695
Lamkin MS, Oppenheim FG (1993) Structural features of salivary function. Crit Rev Oral Biol Med 4(3–4):251–259
Hay DI, Smith DJ, Schluckebier SK, Moreno EC (1984) Relationship between concentration of human salivary statherin and inhibition of calcium phosphate precipitation in stimulated human parotid saliva. J Dent Res 63(6):857–863
Isola M, Cossu M, Diana M, Isola R, Loy F, Solinas P, Lantini MS (2012) Diabetes reduces statherin in human parotid: immunogold study and comparison with submandibular gland. Oral Dis 18(4):360–364
Isola M, Lantini M, Solinas P, Diana M, Isola R, Loy F, Cossu M (2011) Diabetes affects statherin expression in human labial glands. Oral Dis 17(7):685–689
Mednieks MI, Szczepanski A, Clark B, Hand AR (2009) Protein expression in salivary glands of rats with streptozotocin diabetes. Int J Exp Pathol 90(4):412–422
Li J, Helmerhorst EJ, Yao Y, Nunn ME, Troxler RF, Oppenheim FG (2004) Statherin is an in vivo pellicle constituent: identification and immuno-quantification. Arch Oral Biol 49(5):379–385
Niemi LD, Johansson I (2004) Salivary statherin peptide-binding epitopes of commensal and potentially infectious Actinomyces spp. delineated by a hybrid peptide construct. Infect Immun 72(2):782–787
Tsai H, Bobek LA (1998) Human salivary histatins: promising anti-fungal therapeutic agents. Crit Rev Oral Biol Med 9(4):480–497
Piludu M, Lantini MS, Cossu M, Piras M, Oppenheim FG, Helmerhorst EJ et al (2006) Salivary histatins in human deep posterior lingual glands (of von Ebner). Arch Oral Biol 51(11):967–973
Puri S, Edgerton M (2014) How does it kill?: understanding the candidacidal mechanism of salivary histatin 5. Eukaryot Cell 13(8):958–964
Bennick A (1982) Salivary proline-rich proteins. Mol Cell Biochem 45(2):83–99
Carlson DM (1988) Proline-rich proteins and glycoproteins: expression of salivary gland multigene families. Biochimie 70(11):1689–1695
Soares S, Mateus N, de Freitas V (2012) Interaction of different classes of salivary proteins with food tannins. Food Res Int 49(2):807–813
Carlson DM (1993) Salivary proline-rich proteins: biochemistry, molecular biology, and regulation of expression. Crit Rev Oral Biol Med 4(3–4):495–502
Rawlings ND, Barrett AJ (1990) Evolution of proteins of the cystatin superfamily. J Mol Evol 30(1):60–71
Dickinson DP (2002) Salivary (SD-type) cystatins: over one billion years in the making–but to what purpose? Crit Rev Oral Biol Med 13(6):485–508
Kordiš D, Turk V (2009) Phylogenomic analysis of the cystatin superfamily in eukaryotes and prokaryotes. BMC Evol Biol 9:266
Barrett AJ, Fritz H, Grubb A, Isemura S, Järvinen M, Katunuma N et al (1986) Nomenclature and classification of the proteins homologous with the cysteine-proteinase inhibitor chicken cystatin. Biochem J 236:312
Turk V, Stoka V, Turk D (2008) Cystatins: biochemical and structural properties, and medical relevance. Front Biosci 13:5406–5420
Abrahamson M, Alvarez-Fernandez M, Nathanson CM (2003) Cystatins. Biochem Soc Symp 70:179–199
Devos A, De Clercq N, Vercaeren I, Heyns W, Rombauts W, Peeters B (1993) Structure of rat genes encoding androgen-regulated cystatin-related proteins (CRPs): a new member of the cystatin superfamily. Gene 125(2):159–167
Parent AD, Cornwall GA, Liu LY, Smith CE, Hermo L (2011) Alterations in the testis and epididymis associated with loss of function of the cystatin-related epididymal spermatogenic (CRES) protein. J Androl 32(4):444–463
Wang L, Yuan Q, Chen S, Cai H, Lu M, Liu Y, Xu C (2012) Antimicrobial activity and molecular mechanism of the CRES protein. PLoS ONE 7(11):e48368
Lalmanach G, Naudin C, Lecaille F, Fritz H (2010) Kininogens: more than cysteine protease inhibitors and kinin precursors. Biochimie 92(11):1568–1579
Habermann E (1970) Kininogens, bradykinin, kallidin and kallikrein. Handb Exp Pharmacol 25:250–288
Khorchid A, Ikura M (2002) How calpain is activated by calcium. Nat Struct Mol Biol 9:239–241
Ono Y, Sorimachi H (2012) Calpains—an elaborate proteolytic system. Biochim Biophys Acta Proteins Proteom 1824(1):224–236
Schmaier AH (2000) Plasma kallikrein/kinin system: a revised hypothesis for its activation and its physiologic contributions. Curr Opin Hematol 7(5):261–265
Karlsrud TS, Buø L, Aasen AO, Johansen HT (1991) Characterization of kininogens in human malignant ascites. Thromb Res 63(6):641–650
Sharma JN, Al-Banoon A (2012) The role of inflammatory mediator bradykinin in cardiovascular and renal diseases. Sci Rep 1:142
Hojima Y, Maranda B, Moriwaki C, Schachter M (1977) Direct evidence for the location of kallikrein in the striated ducts of the cat’s submandibular gland by the use of specific antibody. J Physiol 268(3):793–801
Heidland A, Röckel A, Schmid G (1979) Salivary kallikrein excretion in hypertension. Klin Wochenschr 57(19):1047–1052
Liu CY, Scott CF, Bagdasarian A, Pierce JV, Kaplan AP, Colman RW (1977) Potentiation of the function of Hageman factor fragments by high molecular weight kininogen. J Clin Invest 60(1):7–17
Paul M, Poyan Mehr A, Kreutz R (2006) Physiology of local renin-angiotensin systems. Physiol Rev 86(3):747–803
Basso N, Terragno NA (2001) History about the discovery of the renin-angiotensin system. Hypertension 38(6):1246–1249
Ian Phillips M, Schmidt-Ott KM (1999) The discovery of renin 100 years ago. Physiology 14(6):271–274
Van Epps HL (2005) Harry Goldblatt and the discovery of renin. J Exp Med 201(9):1351
Fournier D, Luft FC, Bader M, Ganten D, Andrade-Navarro MA (2012) Emergence and evolution of the renin–angiotensin–aldosterone system. J Mol Med (Berl) 90(5):495–508
Kon Y, Endoh D (1999) Renin in exocrine glands of different mouse strains. Anat Histol Embryol 28(4):239–242
Poulsen K, Jacobsen J (1983) The biochemistry of aggression-provoked renin. Clin Exp Hypertens A 5(7–8):969–973
Mercan R, Bıtık B, Tezcan ME, Kaya A, Tufan A, Özturk MA et al (2014) Minimally invasive minor salivary gland biopsy for the diagnosis of amyloidosis in a rheumatology clinic. ISRN Rheumatol 2014:354648
de Paula Eduardo F, de Mello Bezinelli L, de Carvalho DLC, Della-Guardia B, de Almeida MD, Marins LV, Corrêa L (2017) Minor salivary gland biopsy for the diagnosis of familial amyloid polyneuropathy. Neurol Sci 38(2):311–318
Sacsaquispe SJ, Antúnez-de Mayolo EA, Vicetti R, Delgado WA (2011) Detection of AA-type amyloid protein in labial salivary glands. Med Oral Patol Oral Cir Bucal 16(2):e149–e152
Yang GCH, Kuhel WI, Scognamiglio T (2014) Amyloid-rich low grade adenocarcinoma of the parotid: fine-needle aspiration cytology with histologic correlations. Diagn Cytopathol 42(9):798–801
Lechapt-Zalcman E, Authier FJ, Creange A, Voisin MC, Gherardi RK (1999) Labial salivary gland biopsy for diagnosis of amyloid polyneuropathy. Muscle Nerve 22(1):105–107
Bermejo-Pareja F, Antequera D, Vargas T, Molina JA, Carro E (2010) Saliva levels of Abeta1-42 as potential biomarker of Alzheimer’s disease: a pilot study. BMC Neurol 10:108
Lee M, Guo JP, Kennedy K, McGeer EG, McGeer PL (2017) A method for diagnosing alzheimer’s disease based on salivary amyloid-β protein 42 levels. J Alzheimers Dis 55(3):1175–1182
Ralhan R, Desouza LV, Matta A, Chandra Tripathi S, Ghanny S, Dattagupta S et al (2009) iTRAQ-multidimensional liquid chromatography and tandem mass spectrometry-based identification of potential biomarkers of oral epithelial dysplasia and novel networks between inflammation and premalignancy. J Proteome Res 8(1):300–309
Gröschl M (2008) Current status of salivary hormone analysis. Clin Chem 54(11):1759–1769
Abikshyeet P, Ramesh V, Oza N (2012) Glucose estimation in the salivary secretion of diabetes mellitus patients. Diabetes Metab Syndr Obes 5:149–154
Nayak S, Bhad Patil WA, Doshi UH (2014) The relationship between salivary insulin-like growth factor I and quantitative cervical maturational stages of skeletal maturity. J Orthod 41(3):170–174
Hassaneen M, Maron JL (2017) Salivary diagnostics in pediatrics: applicability, translatability, and limitations. Front Public Health 5:83
Estrada-Y-Martin RM, Orlander PR (2011) Salivary cortisol can replace free serum cortisol measurements in patients with septic shock. Chest 140(5):1216–1222
Perogamvros I, Owen LJ, Newell-Price J, Ray DW, Trainer PJ, Keevil BG (2009) Simultaneous measurement of cortisol and cortisone in human saliva using liquid chromatography–tandem mass spectrometry: application in basal and stimulated conditions. J Chromatogr B Analyt Technol Biomed Life Sci 877(29):3771–3775
Meulenberg PM, Hofman JA (1990) Differences between concentrations of salivary cortisol and cortisone and of free cortisol and cortisone in plasma during pregnancy and postpartum. Clin Chem 36(1):70–75
Malamud D, Rodriguez-Chavez IR (2011) Saliva as a diagnostic fluid. Dent Clin North Am 55(1):159–178
Lewis JG (2006) Steroid analysis in saliva: an overview. Clin Biochem Rev 27(3):139–146
Lee JM, Garon E, Wong DT (2009) Salivary diagnostics. Orthod Craniofac Res 12(3):206–211
Kolka CM, Bergman RN (2012) The barrier within: endothelial transport of hormones. Physiology (Bethesda) 27(4):237–247
Ekström J (1989) Autonomic control of salivary secretion. Proc Finn Dent Soc 85(4–5):323–331; 361–363
Garrett JR, Kidd A (1993) The innervation of salivary glands as revealed by morphological methods. Microsc Res Tech 26(1):75–91
Bhattacharya S, Verrill D, Giovannucci D (2011) The role of P2X4 receptors in calcium-mediated exocytosis in parotid acinar cells. Biophys J 100(3):p258a
Ferreira JN, Hoffman MP (2013) Interactions between developing nerves and salivary glands. Organogenesis 9(3):199–205
Eneroth CM, Hökfelt T, Norberg KA (1969) The role of the parasympathetic and sympathetic innervation for the secretion of human parotid and submandibular glands. Acta Otolaryngol 68(5):369–375
Norberg KA, Eneroth CM, Hökfelt T (1969) The significance of the autonomic innervation for the salivary secretion in the human parotid and submandibular glands. Acta Otolaryngol Suppl 263:193–194
Hettigoda NS, Fong AY, Badoer E, McKinley MJ, Oldfield BJ, Allen AM (2015) Identification of CNS neurons with polysynaptic connections to both the sympathetic and parasympathetic innervation of the submandibular gland. Brain Struct Funct 220(4):2103–2120
Sadi H, Finkelman M, Rosenberg M (2013) Salivary cortisol, salivary alpha amylase, and the dental anxiety scale. Anesth Prog 60(2):46–53
Ship JA, Fischer DJ (1997) The relationship between dehydration and parotid salivary gland function in young and older healthy adults. J Gerontol A Biol Sci Med Sci 52(5):M310–M319
Taubert M, Davies EMR, Back I (2007) Dry mouth. BMJ 334(7592):534
Ishikawa Y, Cho G, Yuan Z, Skowronski MT, Pan Y, Ishida H (2006) Water channels and zymogen granules in salivary glands. J Pharmacol Sci 100:495–512
Emmelin N (1987) Nerve interactions in salivary glands. J Dent Res 66(2):509–517
Proctor GB, Carpenter GH (2014) Salivary secretion: mechanism and neural regulation. Monogr Oral Sci 24:14–29
Chopra DP, Xue-Hu IC (1993) Secretion of alpha-amylase in human parotid gland epithelial cell culture. J Cell Physiol 155(2):223–233
Keating C (2004) The effects of dopamine agonists and antagonists on the secretory responses in the salivary glands of the locust (Locusta migratoria). J Insect Physiol 50(1):17–23
Michalek R, Templeton D (1986) The role of dopamine in salivation in the rat parotid gland. Gen Pharmacol Vascular Syst 17(4):473–476
Evans AM, Green KL (1990) Characterization of the dopamine receptor mediating the hyperpolarization of cockroach salivary gland acinar cells in vitro. Br J Pharmacol 101(1):103–108
Baumann O, Dames P, Kühnel D, Walz B (2002) Distribution of serotonergic and dopaminergic nerve fibers in the salivary gland complex of the cockroach Periplaneta americana. BMC Physiol 2:9
Just F, Walz B (1996) The effects of serotonin and dopamine on salivary secretion by isolated cockroach salivary glands. J Exp Biol 199(Pt 2):407–413
Ghafoor M (2012) Sjögren’s before Sjögren: did Henrik Sjögren (1899–1986) really discover Sjögren’s disease? J Maxillofac Oral Surg 11(3):373–374
Igoe A, Scofield RH (2013) Autoimmunity and infection in Sjögren’s syndrome. Curr Opin Rheumatol 25(4):480–487
Baccaglini L, Baum BJ (2008) Hypothesis: Sjögren’s syndrome: a possible pathogenetic mechanism involving somatostatin. Oral Dis 6(5):264–266
Abdulnour-Nakhoul S, Nakhoul HN, Kalliny MI, Gyftopoulos A, Rabon E, Doetjes R et al (2011) Ion transport mechanisms linked to bicarbonate secretion in the esophageal submucosal glands. Am J Physiol Regul Integr Comp Physiol 301(1):R83–R96
Joo NS, Krouse ME, Wu JV, Saenz Y, Jayaraman S, Verkman AS, Wine JJ (2001) HCO3− transport in relation to mucus secretion from submucosal glands. JOP 2(4):280–284
Orlando RC (2010) The integrity of the esophageal mucosa. Balance between offensive and defensive mechanisms. Best Pract Res Clin Gastroenterol 24(6):873–882
Sugimachi K, Sumiyoshi K, Nozoe T, Yasuda M, Watanabe M, Kitamura K et al (1995) Carcinogenesis and histogenesis of esophageal carcinoma. Cancer 75(6):1440–1445
Kuwano H, Ueo H, Sugimachi K, Inokuchi K, Toyoshima S, Enjoji M (1985) Glandular or mucus-secreting components in squamous cell carcinoma of the esophagus. Cancer 56(3):514–518
Long JD, Orlando RC (1999) Esophageal submucosal glands: structure and function. Am J Gastroenterol 94(10):2818–2824
Shafik A, Shafik AA, El Sibai O, Mostafa RM (2004) Effect of straining on diaphragmatic crura with identification of the straining-crural reflex. The “reflex theory” in gastroesophageal competence. BMC Gastroenterol 4:24
Goyal RK, Chaudhury A (2008) Physiology of normal esophageal motility. J Clin Gastroenterol 42(5):610–619
Abdulnour-Nakhoul S, Nakhoul NL, Wheeler SA, Wang P, Swenson ER, Orlando RC (2005) HCO3− secretion in the esophageal submucosal glands. Am J Physiol Gastrointest Liver Physiol 288(4):G736–G744
Kongara KR, Soffer EE (1999) Saliva and esophageal protection. Am J Gastroenterol 94(6):1446–1452
Akiba Y, Mizumori M, Kuo M, Ham M, Guth PH, Engel E, Kaunitz JD (2008) CO2 chemosensing in rat oesophagus. Gut 57(12):1654–1664
Zhuang L, Peng J-B, Tou L, Takanaga H, Adam RM, Hediger MA, Freeman MR (2002) Calcium-selective ion channel, CaT1, is apically localized in gastrointestinal tract epithelia and is aberrantly expressed in human malignancies. Lab Invest 82:1755–1764
Lord RVN, Park JM, Wickramasinghe K, DeMeester SR, Oberg S, Salonga D et al (2003) Vascular endothelial growth factor and basic fibroblast growth factor expression in esophageal adenocarcinoma and Barrett esophagus. J Thorac Cardiovasc Surg 125(2):246–253
Fujiwara Y, Higuchi K, Takashima T, Hamaguchi M, Hayakawa T, Tominaga K et al (2006) Roles of epidermal growth factor and Na+/H+ exchanger-1 in esophageal epithelial defense against acid-induced injury. Am J Physiol Gastrointest Liver Physiol 290(4):G665–G673
Modlin IM, Lane G, Johnson SP, Schoenfeld PS, Allen J, Brill JV (2008) American gastroenterological association medical position statement on the management of gastroesophageal reflux disease. Gastroenterology 135:1383–1391
Odze RD (2005) Unraveling the mystery of the gastroesophageal junction: a pathologist’s perspective. Am J Gastroenterol 100(8):1853–1867
Chandrasoma P (2005) Controversies of the cardiac mucosa and Barrett’s oesophagus. Histopathology 46(4):361–373
Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R, Global Consensus Group (2006) The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 101(8):1900–1920, 1943
Modlin IM, Hunt RH, Malfertheiner P, Moayyedi P, Quigley EM, Tytgat GNJ et al (2009) Diagnosis and management of non-erosive reflux disease—the Vevey NERD consensus group. Digestion 80(2):74–88
Ang D, Sifrim D, Tack J (2008) Mechanisms of heartburn. Nat Rev Gastroenterol Hepatol 5:383–392
Naini BV, Souza RF, Odze RD (2016) Barrett’s esophagus: a comprehensive and contemporary review for pathologists. Am J Surg Pathol 40(5):e45–e66
Reid BJ, Li X, Galipeau PC, Vaughan T (2010) Barrett’s oesophagus and oesophageal adenocarcinoma: time for a new synthesis. Nat Rev Cancer 10(2):87–101
Barbon C, Mungo B, Molena D, Yang SC (2015) Severe reflux-induced esophagitis. In: Pawlik TM, Maithel SK, Merchant NB (eds) Gastrointestinal surgery. Springer, New York
Hirano I (2011) Eosinophilic esophagitis and gastroesophageal reflux disease: there and back again. Clin Gastroenterol Hepatol 9(2):99–101
Hershcovici T, Fass R (2010) Nonerosive reflux disease (NERD)—an update. J Neurogastroenterol Motil 16(1):8–21
Gao F, Gao Y, Chen X, Qian J, Zhang J (2017) Comparison of oesophageal function tests between Chinese non-erosive reflux disease and reflux hypersensitivity patients. BMC Gastroenterol 17:67
Gindea C, Birla R, Hoara P, Caragui A, Constantinoiu S (2014) Barrett esophagus: history, definition and etiopathogeny. J Med Life 7(3):23–30
Van Eyken P (2000) Definition of Barrett’s oesophagus. Acta Gastroenterol Belg 63(1):10–12
Schubert ML, Peura DA (2008) Control of gastric acid secretion in health and disease. Gastroenterology 134:1842
Rowland KJ, Choi PM, Warner BW (2013) The role of growth factors in intestinal regeneration and repair in necrotizing enterocolitis. Semin Pediatr Surg 22(2):101–111
Bimczok D, Kao JY, Zhang M, Cochrun S, Mannon P, Peter S et al (2015) Human gastric epithelial cells contribute to gastric immune regulation by providing retinoic acid to dendritic cells. Mucosal Immunol 8:533–544
Taupin D, Podolsky DK (2003) Trefoil factors: initiators of mucosal healing. Nat Rev Mol Cell Biol 4:721–732
Pakurar AS, Bigbee JW (2004) Digital histology: an interactive CD atlas with review text. Wiley, Hoboken
Wright NA (2000) Epithelial stem cell repertoire in the gut: clues to the origin of cell lineages, proliferative units and cancer. Int J Exp Path 81:117–143
Miyake K, Tanaka T, McNeil PL (2006) Disruption-induced mucus secretion: repair and protection. PLoS Biol 4(9):e276
Roberts NB (2006) Human pepsins—their multiplicity, function and role in reflux disease. Aliment Pharmacol Ther 24(2):2–9
Cui G, Waldum HL (2007) Physiological and clinical significance of enterochromaffin-like cell activation in the regulation of gastric acid secretion. World J Gastroenterol 28:493–496
Liu Y, Vosmaer GDC, Tytgat GNJ, S-d Xiao, Ten Kate FJW (2005) Gastrin (G) cells and somatostatin (D) cells in patients with dyspeptic symptoms: Helicobacter pylori associated and non-associated gastritis. J Clin Pathol 58(9):927–931
Sun F-P, Song Y-G, Cheng W, Zhao T, Yao Y-L (2002) Gastrin, somatostatin, G and D cells of gastric ulcer in rats. World J Gastroenterol 8(2):375–378
Park SM, Park HS (1993) G- and D-cell populations, serum and tissue concentrations of gastrin and somatostatin in patients with peptic ulcer diseases. Korean J Intern Med 8(1):1–7
Sekler I, Kobayashi S, Kopito RR (1996) A cluster of cytoplasmic histidine residues specifies pH dependence of the AE2 plasma membrane anion exchanger. Cell 86(6):929–935
Schreiber S, Garten D, Nguyen TH, Konradt M, Bücker R, Scheid P (2007) In situ measurement of pH in the secreting canaliculus of the gastric parietal cell and adjacent structures. Cell Tissue Res 329(2):313–320
Phan J, Benhammou JN, Pisegna JR (2015) Gastric hypersecretory states: investigation and management. Curr Treat Options Gastroenterol 13(4):386–397
Browning KN, Travagli RA (2014) Central nervous system control of gastrointestinal motility and secretion and modulation of gastrointestinal functions. Compr Physiol 4(4):1339–1368
Konturek SJ, Kwiecien N, Obtulowicz W, Mikos E, Sito E, Oleksy J, Popiela T (1979) Cephalic phase of gastric secretion in healthy subjects and duodenal ulcer patients: role of vagal innervation. Gut 20(10):875–881
Håkanson R, Hedenbro J, Liedberg G, Sundler F, Vallgren S (1980) Mechanisms of gastric acid secretion after pylorus and oesophagus ligation in the rat. J Physiol 305:139–149
Sachs G, Zeng N, Prinz C (1997) Physiology of isolated gastric endocrine cells. Annu Rev Physiol 59:243–256
Fokina A, Konturek SJ, Kwiecien N, Radecki T (1979) Role of gastric antrum in gastric and intestinal phases of gastric secretion in dogs. J Physiol 295:229–239
Kester RC (1975) The intestinal phase of gastric secretion. Ann R Coll Surg Engl 56(5):231–245
Kelly KA, Nyhus LM, Harkins HN (1964) The vagal nerve and the intestinal phase of gastric secretion. Gastroenterology 46(2):163–166
Helander HF, Keeling DJ (1993) Cell biology of gastric acid secretion. Baillieres Clin Gastroenterol 7(1):1–21
Chew CS, Nakamura K, Ljungström M (1992) Calcium signaling mechanisms in the gastric parietal cell. Yale J Biol Med 65(6):561–623
Helander HF (1988) Physiology and pharmacology of the parietal cell. Baillieres Clin Gastroenterol 2(3):539–554
Yao X, Forte JG (2003) Cell biology of acid secretion by the parietal cell. Annu Rev Physiol 65:103–131
Hamada E, Nakajima T, Hata Y, Hazama H, Iwasawa K, Takahashi M et al (1997) Effect of caffeine on mucus secretion and agonist-dependent Ca2+ mobilization in human gastric mucus secreting cells. Biochim Biophys Acta Mol Cell Res 1356(2):198–206
Laddha SS, Wadodkar SG, Meghal SK (2009) cAMP-dependent phosphodiesterase inhibition and SAR studies on novel 6,8-disubstituted 2-phenyl-3-(substituted benzothiazole-2-yl)-4[3H]-quinazolinone. Med Chem Res 18(4):268–276
Sette C, Conti M (1996) Phosphorylation and activation of a cAMP-specific phosphodiesterase by the cAMP-dependent protein kinase—involvement of serine 54 in the enzyme activation. J Biol Chem 271:16526–16534
Koertge N (ed) (2007) New dictionary of scientific biography, 1st edn. Charles Scribners & Sons, Detroit
Bourgoin SM (2012) Encyclopedia of world biography, 2nd edn. Gale Research, Detroit
Bennett MR (2000) The concept of transmitter receptors: 100 years on. Neuropharmacology 39:523–546
Maehle A-H (2004) Receptive substances: John Newport Langley (1852–1925) and his Path to a receptor theory of drug action. Med Hist 48:153–174
Langley JN (1905) On the reaction of cells and of nerve-endings to certain poisons, chiefly as regards the reaction of striated muscle to nicotine and to curari. J Physiol 33:374–413
Rubin RP (2007) A brief history of great discoveries in pharmacology: in celebration of the centennial anniversary of the founding of the American Society of Pharmacology and Experimental Therapeutics. Pharmacol Rev 59(4):289–359
Maehle A-H (2009) A binding question: the evolution of the receptor concept. Endeavour 33(4):135–140
Boes CJ (2014) Langley, John Newport. In: Aminoff MJ, Daroff RB (eds) Encyclopedia of the neurological sciences, 2nd edn. Elsevier, MA
Sawaya AC, Costa YD, Mazzafera P (2015) Unraveling the biosynthesis of pilocarpine in Pilocarpus microphyllus. Nat Prod Commun 10(5):721–724
Sawaya AC, Abreu IN, Andreazza NL, Eberlin MN, Mazzafera P (2008) HPLC-ESI-MS/MS of imidazole alkaloids in Pilocarpus microphyllus. Molecules 13(7):1518–1529
Dias DA, Urban S, Roessner U (2012) A historical overview of natural products in drug discovery. Metabolites 2(2):303–336
Richards D, Aronson J, Reynolds DJ, Coleman J (2011) Oxford handbook of practical drug therapy, 2nd edn. Oxford University Press, Oxford
Lidums I, Hebbard GS, Hollowaya RH (2000) Effect of atropine on proximal gastric motor and sensory function in normal subjects. Gut 47:30–36
Moulton BC, Fryer AD (2011) Muscarinic receptor antagonists, from folklore to pharmacology; finding drugs that actually work in asthma and COPD. Br J Pharmacol 163(1):44–52
O’Brien RD (1974) Atropine. In: Simpson LL, Curtis DR (eds) Poisons of plant origin. Plenum Press, New York
Schwarzenberger M, Stintzing F, Meyer U, Lindequist U (2012) Biochemical, microbiological and phytochemical studies on aqueous-fermented extracts from Atropa belladonna L. Part 2—phytochemistry. Pharmazie 67(5):460–466
Schwarzenberger M, Stintzing F, Meyer U, Lindequist U (2012) Biochemical, microbiological and phytochemical studies on aqueous-fermented extracts from Atropa belladonna L. Part 1—biochemistry and microbiology. Pharmazie 67(4):331–344
Lee MR (2007) Solanaceae IV: Atropa belladonna, deadly nightshade. J R Coll Physicians Edinb 37(1):77–84
Rajput H (2013) Effects of Atropa belladonnas an anti-cholinergic. Nat Prod Chem Res 1:104
Blackshaw LA (2008) New insights in the neural regulation of the lower oesophageal sphincter. Eur Rev Med Pharmacol Sci 12(1):33–39
Mittal R, Chiareli C, Liu J, Holloway R, Dixon W (1997) Atropine inhibits gastric distension and pharyngeal receptor mediated lower oesophageal sphincter relaxation. Gut 41(3):285–290
Zhang Q, Lehmann A, Rigda R, Dent J, Holloway RH (2002) Control of transient lower oesophageal sphincter relaxations and reflux by the GABAB agonist baclofen in patients with gastro-oesophageal reflux disease. Gut 50(1):19–24
Vakil N (2004) New pharmacological agents for the treatment of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 19:1041–1049
Hirsch DP, Tytgat GNJ, Boeckxstaens GEE (2002) Transient lower oesophageal sphincterrelaxations—a pharmacological target for gastro-oesophageal reflux disease? Aliment Pharmacol Ther 16:17–26
Li S, Shi S, Chen F, Lin J (2014) The effects of baclofen for the treatment of gastroesophageal reflux disease: a meta-analysis of randomized controlled trials. Gastroenterol Res Pract 2014:307805
Tonini M, De Giorgio R, De Ponti F (2004) Progress with novel pharmacological strategies for gastro-oesophageal reflux disease. Drugs 64(4):347–361
Kahrilas PJ, Boeckxstaens G (2012) Failure of reflux inhibitors in clinical trials: bad drugs or wrong patients? Gut 61(10):1501–1509
Yamato S, Saha JK, Goyal RK (1992) Role of nitric oxide in lower esophageal sphincter relaxation to swallowing. Life Sci 50(17):1263–1272
Tomita R, Tanjoh K, Fujisaki S, Fukuzawa M (2003) Physiological studies on nitric oxide in the lower esophageal sphincter of patients with reflux esophagitis. Hepatogastroenterology 50(49):110–114
Baker DE (2007) Loperamide: a pharmacological review. Rev Gastroenterol Disord 7(3):S11–S18
Ehlert FJ, Pak KJ, Griffin MT (2012) Muscarinic agonists and antagonists: effects on gastrointestinal function. Handb Exp Pharmacol 208:343–374
Borella TL, De Luca LA, Jr Colombari DS, Menani JV (2008) Central muscarinic receptor subtypes involved in pilocarpine-induced salivation, hypertension and water intake. Br J Pharmacol 155(8):1256–1263
Carmine AA, Brogden RN (1985) Pirenzepine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in peptic ulcer disease and other allied diseases. Drugs 30(2):85–126
Boulanger CM, Morrison KJ, Vanhoutte PM (1994) Mediation by M3-muscarinic receptors of both endothelium-dependent contraction and relaxation to acetylcholine in the aorta of the spontaneously hypertensive rat. Br J Pharmacol 112(2):519–524
Watson N, Barnes PJ, Maclagan J (1992) Actions of methoctramine, a muscarinic M2 receptor antagonist, on muscarinic and nicotinic cholinoceptors in guinea-pig airways in vivo and in vitro. Br J Pharmacol 105(1):107–112
Jakubík J, Zimčík P, Randáková A, Fuksová K, El-Fakahany EE, Doležal V (2014) Molecular mechanisms of methoctramine binding and selectivity at muscarinic acetylcholine receptors. Mol Pharmacol 86(2):180–192
Ehlert FJ (1996) The interaction of 4-DAMP mustard with subtypes of the muscarinic receptor. Life Sci 58(22):1971–1978
Holzer P (2009) Opioid receptors in the gastrointestinal tract. Regul Pept 155(1–3):11–17
Leppert W (2012) The impact of opioid analgesics on the gastrointestinal tract function and the current management possibilities. Contemp Oncol (Pozn) 16(2):125–131
Leppert W (2014) Oxycodone/naloxone in the management of patients with pain and opioid-induced bowel dysfunction. Curr Drug Targets 15(1):124–135
Gotfried J, Kataria R, Schey R (2017) The role of cannabinoids on esophageal function—what we know thus far. Cannabis Cannabinoid Res 2(1):252–258
Franklin JM, Carrasco GA (2012) Cannabinoid-induced enhanced interaction and protein levels of serotonin 5-HT(2A) and dopamine D2 receptors in rat prefrontal cortex. J Psychopharmacol 26(10):1333–1347
Franklin JM, Carrasco GA (2013) Cannabinoid receptor agonists upregulate and enhance serotonin 2A (5-HT(2A)) receptor activity via ERK1/2 signaling. Synapse 67(3):145–159
Vandenberg RJ, Frencht CR, Barry PH, Shine J, Schofield PR (1992) Antagonism of ligand-gated ion channel receptors: two domains of the glycine receptor a subunit form the strychnine-binding site. Proc Natl Acad Sci U S A 89:1765–1769
Zhang M, Aguilera D, Das C, Vasquez H, Zage P, Gopalakrishnan V, Wolff J (2007) Measuring cytotoxicity: a new perspective on LC50. Anticancer Res 27(1A):35–38
Guo R, Wang T, Zhou G, Xu M, Yu X, Zhang X et al (2018) Botany, phytochemistry, pharmacology and toxicity of Strychnos nux-vomica L.: a review. Am J Chin Med 46(1):1–23
Gaddum JH (1957) John William Trevan, 1887-1956. Biogr Mem Fellows R Soc 3:273–288
Born S, Levit A, Niv MY, Meyerhof W, Behrens M (2013) The human bitter taste receptor TAS2R10 is tailored to accommodate numerous diverse ligands. J Neurosci 33(1):201–213
Rajendra S, Lynch JW, Schofield PR (1997) The glycine receptor. Pharmacol Ther 73(2):121–146
Duan L, Yang J, Slaughter MM (2009) Caffeine inhibition of ionotropic glycine receptors. J Physiol 587(16):4063–4075
Kuijpers GA, Vergara LA, Calvo S, Yadid G (1994) Inhibitory effect of strychnine on acetylcholine receptor activation in bovine adrenal medullary chromaffin cells. Br J Pharmacol 113(2):471–478
Maehle AH, Prüll CR, Halliwell RF (2002) The emergence of the drug receptor theory. Nat Rev Drug Discov 1(8):637–641
Ehrlich P (1908) Nobel lecture on partial functions of the cell. In: Himmelweit F, Marquardt M, Dale HH (eds) The collected papers of P. Ehrlich, vol III. Pergamon Press, Oxford
Langley JN (1906) On nerve endings and on special excitable substances in cells. Proc R Soc B Biol Sci 70:170–194
Clark AJ (1926) The reaction between acetylcholine and muscle cells. J Physiol 61:530–547
Clark AJ (1926) The antagonism of acetylcholine by atropine. J Physiol 61:547–556
Clark AJ, Raventos J (1937) The antagonism of acetylcholine and of quaternary ammonium salts. Q J Exp Physiol 26:375–392
Verney EB, Barcroft J (1941) Alfred Joseph Clark. 1885–1941. Obit Not Fell R Soc 3(10):969–984
Lees GM (1998) A tribute to the late Hans W. Kosterlitz: ploughing the lone furrow. Can J Physiol Pharmacol 76(3):244–251
Prüll CR (2006) Caught between the old and the new—Walther Straub (1874–1944), the question of drug receptors, and the rise of modern pharmacology. Bull Hist Med 80(3):465–489
Dale HH, Feldberg W, Vogt M (1936) Release of acetylcholine at voluntary motor nerve endings. J Physiol 86:353–380
Loewi O (1921) Über humorale Übertragbarkeit der Herznervenwirkung. I.Mittei-lung (About humoral transmissibility of the cardiac nervous system) Pflügers Arch Ges Physiol 189:239–242
Loewi O (1921) Über humorale Übertragbarkeit der Herznervenwirkung. II. Mittei-lung. Pflügers Arch Ges Physiol 193:201–213
Rang HP (2006) The receptor concept: pharmacology’s big idea. Br J Pharmacol 147(S1):S9–S16
Limbird LE (2004) The receptor concept: a continuing evolution. Mol Interv 4(6):326–336
Ahlquist RP (1948) A study of the adrenotrophic receptors. Am J Physiol 155:586–600
Segal I, Yaakov Y, Adler SN, Blau H, Broide E, Santo M et al (2008) Cystic fibrosis transmembrane conductance regulator ion channel function testing in recurrent acute pancreatitis. J Clin Gastroenterol 42(7):810–814
Ashlock MA, Olson ER (2011) Therapeutics development for cystic fibrosis: a successful model for a multisystem genetic disease. Annu Rev Med 62:107–125
Elborn JS (2007) How can we prevent multisystem complications of cystic fibrosis? Semin Respir Crit Care Med 28(3):303–311
Larsen EH (2002) Hans H. Ussing—scientific work: contemporary significance and perspectives. Biochim Biophys Acta Biomembr 1566(1–2):2–15
Parsons ME, Ganellin CR (2006) Histamine and its receptors. Br J Pharmacol 147(1):S127–S135
Fogel WA (2015) Histamine. In: Parnham M (ed) Encyclopedia of inflammatory diseases. Springer Basel, Switzerland
Petersen H (1991) Histamine and the stomach: introduction. Scand J Gastroenterol 26(180):2–3
Ganellin CR (2011) Personal reflections on Sir James Black (1924–2010) and histamine. Inflamm Res 60(1):103–110
Konturek SJ, Konturek PC, Konturek JW, Plonka M, Czesnikiewicz-Guzik M, Brzozowski T, Bielanski W (2006) Helicobacter pylori and its involvement in gastritis and peptic ulcer formation. J Physiol Pharmacol 57(3):29–50
Black RB, Hole D, Rhodes J (1971) Bile damage to the gastric mucosal barrier: the influence of pH and bile acid concentration. Gastroenterology 61(2):178–184
Black RB, Rhodes J, Hole D (1973) Measurement of bile damage to the gastric mucosa. The relation between the electrical potential difference and transmucosal movement of hydrogen and sodium ion. Am J Dig Dis 18(5):411–415
Black JW, Duncan WA, Durant CJ, Ganellin CR, Parsons EM (1972) Definition and antagonism of histamine H2-receptors. Nature 236:385–390
Black JW, Owen DA, Parsons ME (1975) An analysis of the depressor responses to histamine in the cat and dog: involvement of both H1- and H2-receptors. Br J Pharmacol 54(3):319–324
Ganser AL, Forte JG (1973) K+-stimulated ATPase in purified microsomes of bullfrog oxyntic cells. Biochim Biophys Acta 307:169–180
Ganser AL, Forte JG (1973) Ionophoretic stimulation of K+-ATPase of oxyntic cell microsomes. Biochem Biophys Res Commun 54(2):690–696
Inocente C, Arnulf I, Bastuji H, Thibault-Stoll A, Raoux A, Reimão R et al (2012) Pitolisant, an inverse agonist of the histamine H3 receptor: an alternative stimulant for narcolepsy-cataplexy in teenagers with refractory sleepiness. Clin Neuropharmacol 35(2):55–60
Black J (1988) Drugs from emasculated hormones: the principles of syntopic antagonism. In: Nobel lecture, physiology or medicine
Marx JL (1988) The 1988 nobel prize for physiology or medicine. Science 242(4878):516–517
Prinz C, Kajimura M, Scott D, Helander H, Shin J, Besancon M et al (1992) Acid secretion and the H, K ATPase of stomach. Yale J Biol Med 65(6):577–596
Shin JM, Munson K, Vagin O, Sachs G (2009) The gastric HK-ATPase: structure, function, and inhibition. Pflugers Arch 457(3):609–622
Soumarmon A, Lewin MJ (1986) Gastric (H+, K+)-ATPase. Biochimie 68(12):1287–1291
Sachs G, Shin JM, Vagin O, Lambrecht N, Yakubov I, Munson K (2007) The gastric H, K ATPase as a drug target: past, present, and future. J Clin Gastroenterol 41(2):S226–S242
Song P, Groos S, Riederer B, Feng Z, Krabbenhöft A, Smolka A, Seidler U (2009) KCNQ1 is the luminal K+ recycling channel during stimulation of gastric acid secretion. J Physiol 587(15):3955–3965
Heitzmann D, Warth R (2008) Physiology and pathophysiology of potassium channels in gastrointestinal epithelia. Physiol Rev 88(3):1119–1182
Julio-Kalajzić F, Villanueva S, Burgos J, Ojeda M, Cid LP, Jentsch TJ, Sepúlveda FV (2018) K2P TASK-2 and KCNQ1-KCNE3K+ channels are major players contributing to intestinal anion and fluid secretion. J Physiol 596(3):393–407
Fujii T, Takahashi Y, Ikari A, Morii M, Tabuchi Y, Tsukada K et al (2009) Functional Association between K+-Cl− Cotransporter-4 and H+, K+-ATPase in the apical canalicular membrane of gastric parietal cells. J Biol Chem 284:619–629
Shamburek RD, Schubert ML (1993) Pharmacology of gastric acid inhibition. Baillieres Clin Gastroenterol 7(1):23–54
Geibel JP, Wagner CA, Caroppo R, Qureshi I, Gloeckner J, Manuelidis L et al (2001) The stomach divalent ion-sensing receptor scar is a modulator of gastric acid secretion. J Biol Chem 276(43):39549–39552
Bakker EP (1979) Ionophore antibiotics. Mechanism of action of antibacterial agents. Antibiotics 5(1):67–97
Daniele RP, Holian SK (1976) A potassium ionophore (valinomycin) inhibits lymphocyte proliferation by its effects on the cell membrane. Proc Natl Acad Sci U S A 73(10):3599–3602
Shamoo AE, Goldstein DA (1977) Isolation of ionophores from ion transport systems and their role in energy transduction. Biochim Biophys Acta Rev Biomembr 472(1):13–53
Bühlmann P, Chen LD (2012) Ion-selective electrodes with ionophore-doped sensing membranes. In: Gale PA, Steed JW (eds) Supramolecular chemistry: from molecules to nanomaterials. Wiley, Chichester
Daniele RP, Holian SK, Nowell PC (1978) A potassium ionophore (Nigericin) inhibits stimulation of human lymphocytes by mitogens. J Exp Med 147(2):571–581
Sachs G, Shin JM, Besancon M, Prinz C (1993) The continuing development of gastric acid pump inhibitors. Aliment Pharmacol Ther 7(1):4–12
Banić M, Malfertheiner P, Babić Z, Ostojić R, Kujundzic M, Fatović-Ferenčić S et al (2011) Historical impact to drive research in peptic ulcer disease. Dig Dis 29(5):444–453
Wallmark B, Sachs G, Mardh S, Fellenius E (1983) Inhibition of gastric (H+-K+)-ATPase by the substituted benzimidazole, picoprazole. Biochim Biophys Acta 728:31–38
Fellenius E, Berglindh T, Sachs G, Olbe L, Elander B, Sjostrand SE, Wallmark B (1981) Substituted benzimidazoles inhibit gastric acid secretion by blocking (H++K+)ATPase. Nature 290:159–161
Khan MOF, Deimling MJ, Philip A (2011) Medicinal chemistry and the pharmacy curriculum. Am J Pharm Educ 75(8):161
Olbe L, Carlsson E, Lindberg P (2003) A proton-pump inhibitor expedition: the case histories of omeprazole and esomeprazole. Nat Rev Drug Discov 2:132–139
Shin JM, Vagin O, Munson K, Kidd M, Modlin IM, Sachs G (2008) Molecular mechanisms in therapy of acid-related diseases. Cell Mol Life Sci 65(2):264–281
Lindberg P, Brändström A, Wallmark B, Mattsson H, Rikner L, Hoffmann KJ (1990) Omeprazole: the first proton pump inhibitor. Med Res Rev 10(1):1–54
Munson K, Garcia R, Sachs G (2005) Inhibitor and ion binding sites on the gastric H, K-ATPase. Biochemistry 44(14):5267–5284
Gremse DA (2001) Lansoprazole: pharmacokinetics, pharmacodynamics and clinical uses. Expert Opin Pharmacother 2(10):1663–1670
Simon WA, Herrmann M, Klein T, Shin JM, Huber R, Senn-Bilfinger J, Postius S (2007) Soraprazan: setting new standards in inhibition of gastric acid secretion. J Pharmacol Exp Ther 321(3):866–874
Kim HK, Park SH, Cheung DY, Cho YS, Kim JI, Kim SS et al (2010) Clinical trial: inhibitory effect of revaprazan on gastric acid secretion in healthy male subjects. J Gastroenterol Hepatol 25(10):1618–1625
Owyang C, Green L, Rader D (1983) Colonic inhibition of pancreatic and biliary secretion. Gastroenterology 84(3):470–475
Cumming JH (1975) Absorption and secretion by the colon. Gut 16(4):323–329
Matsumoto M, Ooga T, Kibe R, Aiba Y, Koga Y, Benno Y (2017) Colonic absorption of low-molecular-weight metabolites influenced by the intestinal microbiome: a pilot study. PLoS ONE 12(1):e0169207
Kuthmann E (1957) Johann Conrad Brunner as a university professor & therapeutist. Gesnerus 14(3–4):119–140
Bosmia AN, Tubbs RI, Clapp DC, Batzdorf U, Loukas M, Tubbs RS (2014) Johann Conrad Brunner (1653–1727) and the first description of syringomyelia. Childs Nerv Syst 30(2):193–196
Heitz PU, Kasper M, van Noorden S, Polak JM, Gregory H, Pearse AG (1978) Immunohistochemical localisation of urogastrone to human duodenal and submandibular glands. Gut 19(5):408–413
Kasselberg AG, Orth DN, Gray ME, Stahlman MT (1985) Immunocytochemical localization of human epidermal growth factor/urogastrone in several human tissues. J Histochem Cytochem 33(4):315–322
Hirata Y, Moore GW, Bertagana C, Orth DN (1980) Plasma concentrations of immunoreactive human epidermal growth factor (urogastrone) in man. J Clin Endocrinol Metab 50(3):440–444
Gerbe F, Legraverend C, Jay P (2012) The intestinal epithelium tuft cells: specification and function. Cell Mol Life Sci 69:2907–2917
May R, Qu D, Weygant N, Chandrakesan P, Ali N, Lightfoot SA et al (2014) Brief report: Dclk1 deletion in tuft cells results in impaired epithelial repair after radiation injury. Stem Cells 32(3):822–827
Humphries A, Wright NA (2008) Colonic crypt organization and tumorigenesis. Nat Rev Cancer 8:415–424
Potten CS (1998) Stem cells in gastrointestinal epithelium: numbers, characteristics and death. Philos Trans R Soc Lond B Biol Sci 353(1370):821–830
Baker AM, Cereser B, Melton S, Fletcher AG, Rodriguez-Justo M, Tadrous PJ et al (2014) Quantification of crypt and stem cell evolution in the normal and neoplastic human colon. Cell Rep 8(4):940–947
van der Flier LG, Clevers H (2009) Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol 71(1):241–260
Leung PS (2010) Physiology of the pancreas. The renin-angiotensin system: current research progress in the pancreas volume 690 of the series advances in experimental medicine and biology. Springer, Dordrecht
Babu CSR, Sharma M (2014) Biliary tract anatomy and its relationship with venous drainage. J Clin Exp Hepatol 4(1):S18–S26
Allescher HD (1989) Papilla of vater: structure and function. Endoscopy 21(1):324–329
Behar J (2013) Physiology and pathophysiology of the biliary tract: the gallbladder and sphincter of Oddi–a review. ISRN Physiol 2013:837630
Ishiguro H, Yamamoto A, Nakakuki M, Yi L, Ishiguro M, Yamaguchi M et al (2012) Physiology and pathophysiology of bicarbonate secretion by pancreatic duct epithelium. Nagoya J Med Sci 74(1–2):1–18
Chang EB, Leung PS (2014) Pancreatic physiology. In: Leung PS (ed) The gastrointestinal system. Springer, Dordrecht
Adelson JW, Miller PE (1989) Heterogeneity of the exocrine pancreas. Am J Physiol Gastrointest Liver Physiol 256(5):G817–G825
Naruse S, Kitagawa M, Ishiguro H, Hayakawa T (2002) Feedback regulation of pancreatic secretion by peptide YY. Peptides 23(2):359–365
Singer MV, Niebergall-Roth E (2009) Secretion from acinar cells of the exocrine pancreas: role of enteropancreatic reflexes and cholecystokinin. Cell Biol Int 33(1):1–9
Verspohl EJ, Tacke R, Mutschler E, Lambrecht G (1990) Muscarinic receptor subtypes in rat pancreatic islets: binding and functional studies. Eur J Pharmacol 178(3):303–311
Low JT, Shukla A, Thorn P (2010) Pancreatic acinar cell: new insights into the control of secretion. Int J Biochem Cell Biol 42(10):1586–1589
Pandol SJ (2010) The exocrine pancreas. Morgan & Claypool Life Sciences, San Rafael
Gray MA, Greenwell JR, Argent BE (1990) The role of ion channels in the mechanism of pancreatic bicarbonate secretion. In: Young JA, Wong PYD (eds) Epithelial secretion of water and electrolytes. Springer, Heidelberg
Cotton CU (2000) Basolateral potassium channels and epithelial ion transport. Am J Respir Cell Mol Biol 23(3):270–272
Banales JM, Gradilone SA (2009) Primers on molecular pathways—ion channels: key regulators of pancreatic physiology. Pancreatology 9(5):556–559
Thévenod F (2005) Ion channels in secretory granules of the pancreas: molecular identification and their role in regulated secretion. In: Schultz C (ed) Defects of secretion in cystic fibrosis. Advances in experimental medicine and biology. Springer, Boston
Kosters A, Karpen SJ (2008) Bile acid transporters in health and disease. Xenobiotica 38(7–8):1043
Kuipers F, Bloks VW, Groen AK (2014) Beyond intestinal soap—bile acids in metabolic control. Nat Rev Endocrinol 10:488–498
Martínez-Augustin O, de Medina FS (2008) Intestinal bile acid physiology and pathophysiology. World J Gastroenterol 14(37):5630–5640
Esteller A (2008) Physiology of bile secretion. World J Gastroenterol 14(37):5641–5649
Rao RK, Samak G (2013) Bile duct epithelial tight junctions and barrier function. Tissue Barriers 1(4):e25718
Strazzabosco M (1997) Transport systems in cholangiocytes: their role in bile formation and cholestasis. Yale J Biol Med 70(4):427–434
Boyer JL (2013) Bile formation and secretion. Compr Physiol 3(3):1035–1078
Kanz MF (2010) Anatomy and physiology of the biliary epithelium. In: McQueen CA (ed) Comprehensive toxicology, 2nd edn. Elsevier, MA
Nagahashi M, Shirai Y, Wakai T, Sakata J, Ajioka Y, Hatakeyama K (2007) Perimuscular connective tissue contains more and larger lymphatic vessels than the shallower layers in human gallbladders. World J Gastroenterol 13(33):4480–4483
Okada K-I, Kijima H, Imaizumi T, Hirabayashi K, Matsuyama M, Yazawa N et al (2012) Clinical significance of wall invasion pattern of subserosa-invasive gallbladder carcinoma. Oncol Rep 28(5):1531–1536
Baumann C (2015) The Physiologist Ewald Hering (1834–1918): curriculum vitae. Strabismus 23(3):135–140
Ivy AC (1934) The physiology of the gall bladder. Physiol Rev 14(1):1–102
Tietz PS, Chen X-M, Gong A-Y, Huebert RC, Masyuk A, Masyuk T et al (2002) Experimental models to study cholangiocyte biology. World J Gastroenterol 8(1):1–4
Tanimizu N, Miyajima A, Mostov KE (2007) Liver progenitor cells develop cholangiocyte-type epithelial polarity in three-dimensional culture. Mol Biol Cell 18(4):1472–1479
Tabibian JH, Masyuk AI, Masyuk TV, O’Hara SP, LaRusso NF (2013) Physiology of cholangiocytes. Compr Physiol 3(1):541–565
Tietz P, Levine S, Holman R, Fretham C, Larusso NF (1997) Characterization of apical and basolateral plasma membrane domains derived from cultured rat cholangiocytes. Analyt Biochem 254(2):192–199
Tietz PS, Larusso NF (2006) Cholangiocyte biology. Curr Opin Gastroenterol 22(3):279–287
Baiocchi L, LeSage G, Glaser S, Alpini G (1999) Regulation of cholangiocyte bile secretion. J Hepatol 31(1):179–191
Tormey JMcD, Diamond JM (1967) The ultrastructural route of fluid transport in rabbit gall bladder. J Gen Physiol 50(8):2031–2060
Alrefai WA, Gill RK (2007) Bile acid transporters: structure, function, regulation and pathophysiological implications. Pharm Res 24(10):1803–1823
Omenetti A, Yang L, Gainetdinov RR, Guy CD, Choi SS, Chen W et al (2011) Paracrine modulation of cholangiocyte serotonin synthesis orchestrates biliary remodeling in adults. Am J Physiol Gastrointest Liver Physiol 300(2):G303–G315
Syal G, Fausther M, Dranoff JA (2012) Advances in cholangiocyte immunobiology. Am J Physiol Gastrointest Liver Physiol 303(10):G1077–G1086
van Mil SWC, van Oort MM, van den Berg IET, Berger R, Houwen RHJ, Klomp LWJ (2004) D1FIC1 is expressed at apical membranes of different epithelial cells in the digestive tract and is induced in the small intestine during postnatal development of mice. Pediatr Res 56:981–987
Arrese M, Ananthananarayanan M, Suchy FJ (1998) Hepatobiliary transport: molecular mechanisms of development and cholestasis. Pediatr Res 44:141–147
Srivastava A (2014) Progressive familial intrahepatic cholestasis. J Clin Exp Hepatol 4(1):25–36
Frankenberg T, Miloh T, Chen FY, Ananthanarayanan M, Sun AQ, Balasubramaniyan N et al (2008) The membrane protein ATPase class I type 8B member 1 signals through protein kinase C zeta to activate the farnesoid X receptor. Hepatology 48(6):1896–1905
Suchy FJ, Ananthanarayanan M (2006) Bile salt excretory pump: biology and pathobiology. J Pediatr Gastroenterol Nutr 43(1):S10–S16
Boyer J (1996) Bile duct epithelium: frontiers in transport physiology. Am J Physiol 270(1 Pt 1):G1–G5
Marinelli RA, Tietz PS, Pham LD, Rueckert L, Agre P, LaRusso NF (1999) Secretin induces the apical insertion of aquaporin-1 water channels in rat cholangiocytes. Am J Physiol 276(1 Pt 1):G280–G286
Melero S, Spirlì C, Zsembery A, Medina JF, Joplin RE, Duner E et al (2002) Defective regulation of cholangiocyte Cl−/HCO3(−) and Na+/H+ exchanger activities in primary biliary cirrhosis. Hepatology 35(6):1513–1521
Mann R, Bhathal PS, Bell C (1991) Aminergic innervation of the gall bladder in man and dog. Clin Auton Res 1(3):205–213
Nelson DK, Glasbrenner B, Dahmen G, Riepl RL, Malfertheiner P, Adler G (1996) M1 muscarinic mechanisms regulate intestinal-phase gallbladder physiology in humans. Am J Physiol Gastrointest Liver Physiol 271(5):G824–G830
Jordan PH Jr (1964) Physiology of bile secretion. Am J Surg 107(2):367–370
Spirlì C, Fabris L, Duner E, Fiorotto R, Ballardini G, Roskams T et al (2003) Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes. Gastroenterology 124(3):737–753
Tabibian JH, Trussoni CE, O’Hara SP, Splinter PL, Heimbach JK, LaRusso NF (2014) Characterization of cultured cholangiocytes isolated from livers of patients with primary sclerosing cholangitis. Lab Invest 94(10):1126–1133
Tabibian JH, O’Hara SP, Splinter PL, Trussoni CE, LaRusso NF (2014) Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis. Hepatology 59(6):2263–2275
Park J, Gores GJ, Patel T (1999) Lipopolysaccharide induces cholangiocyte proliferation via an interleukin-6-mediated activation of p44/p42 mitogen-activated protein kinase. Hepatology 29(4):1037–1043
Okado-Matsumoto A, Matsumoto A, Fujii J, Taniguchi N (2000) Effect of cAMP on inducible nitric oxide synthase gene expression: its dual and cell-specific functions. Antioxid Redox Signal 2(4):631–642
Utter A, Goss F (1997) Exercise and gall bladder function. Sports Med 23(4):218–227
Tierney S, Pitt HA, Lillemoe KD (1993) Physiology and pathophysiology of gallbladder motility. Surg Clin North Am 73(6):1267–1290
Hofmann AF (2007) Biliary secretion and excretion in health and disease: current concepts. Ann Hepatol 6(1):15–27
Li M, Ali SM, Umm-a-OmarahGilani S, Liu J, Li Y-Q, Zuo X-L (2014) Kudo’s pit pattern classification for colorectal neoplasms: a meta-analysis. World J Gastroenterol 20(35):12649–12656
Liu HH, Kudo SE, Juch JP (2003) Pit pattern analysis by magnifying chromoendoscopy for the diagnosis of colorectal polyps. J Formos Med Assoc 102(3):178–182
Gunduz-Demir C, Kandemir M, Tosun AB, Sokmensuer C (2010) Automatic segmentation of colon glands using object-graphs. Med Image Anal 14(1):1–12
Binder HJ, Rajendran V, Sadasivan V, Geibel JP (2005) Bicarbonate secretion: a neglected aspect of colonic ion transport. J Clin Gastroenterol 39(4 Suppl 2):S53–S58
Macleod RJ (2013) CaSR function in the intestine: hormone secretion, electrolyte absorption and secretion, paracrine non-canonical Wnt signaling and colonic crypt cell proliferation. Best Pract Res Clin Endocrinol Metab 27(3):385–402
Binder HJ (2010) Role of colonic short-chain fatty acid transport in diarrhea. Annu Rev Physiol 72:297–313
Milla PJ (2009) Advances in understanding colonic function. J Pediatr Gastroenterol Nutr 48(2):S43–S45
Hedemann MS, Kristiansen E, Brunsgaard G (2002) Morphology of the large intestine of the pig: haustra versus taenia. Ann Anat 184(4):401–403
Tang L, Peng M, Liu L, Chang W, Binder HJ, Cheng SX (2015) Calcium-sensing receptor stimulates Cl(−)- and SCFA-dependent but inhibits cAMP-dependent HCO3(−) secretion in colon. Am J Physiol Gastrointest Liver Physiol 308(10):G874–G883
Brownlee IA, Havler ME, Dettmar PW, Allen A, Pearson JP (2003) Colonic mucus: secretion and turnover in relation to dietary fibre intake. Proc Nutr Soc 62(1):245–249
Vidyasagar S, Rajendran VM, Binder HJ (2004) Three distinct mechanisms of HCO3− secretion in rat distal colon. Am J Physiol Cell Physiol 287(3):C612–C621
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG, part of Springer Nature
About this chapter
Cite this chapter
Welcome, M.O. (2018). Gastrointestinal Exocrine (Lumencrine) Secretions. The Reception Theory as the Basis for Developing the First Antisecretory Pharmacotherapy Drugs. In: Gastrointestinal Physiology. Springer, Cham. https://doi.org/10.1007/978-3-319-91056-7_11
Download citation
DOI: https://doi.org/10.1007/978-3-319-91056-7_11
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-91055-0
Online ISBN: 978-3-319-91056-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)