scholarly journals Molecular Mechanism of Pancreatic and Salivary Gland Fluid and HCO3−Secretion

2012 ◽  
Vol 92 (1) ◽  
pp. 39-74 ◽  
Author(s):  
Min Goo Lee ◽  
Ehud Ohana ◽  
Hyun Woo Park ◽  
Dongki Yang ◽  
Shmuel Muallem
Keyword(s):  
Salivary Glands ◽  
Molecular Mechanism ◽  
Acinar Cells ◽  
Duct Cell ◽  
Fluid Secretion ◽  
Relative Volume ◽  
Electrolyte Composition ◽  
Cell Functions ◽  
Secretory Glands ◽  
High Concentrations

Fluid and HCO3−secretion is a vital function of all epithelia and is required for the survival of the tissue. Aberrant fluid and HCO3−secretion is associated with many epithelial diseases, such as cystic fibrosis, pancreatitis, Sjögren's syndrome, and other epithelial inflammatory and autoimmune diseases. Significant progress has been made over the last 20 years in our understanding of epithelial fluid and HCO3−secretion, in particular by secretory glands. Fluid and HCO3−secretion by secretory glands is a two-step process. Acinar cells secrete isotonic fluid in which the major salt is NaCl. Subsequently, the duct modifies the volume and electrolyte composition of the fluid to absorb the Cl−and secrete HCO3−. The relative volume secreted by acinar and duct cells and modification of electrolyte composition of the secreted fluids varies among secretory glands to meet their physiological functions. In the pancreas, acinar cells secrete a small amount of NaCl-rich fluid, while the duct absorbs the Cl−and secretes HCO3−and the bulk of the fluid in the pancreatic juice. Fluid secretion appears to be driven by active HCO3−secretion. In the salivary glands, acinar cells secrete the bulk of the fluid in the saliva that is driven by active Cl−secretion and contains high concentrations of Na+and Cl−. The salivary glands duct absorbs both the Na+and Cl−and secretes K+and HCO3−. In this review, we focus on the molecular mechanism of fluid and HCO3−secretion by the pancreas and salivary glands, to highlight the similarities of the fundamental mechanisms of acinar and duct cell functions, and to point out the differences to meet gland-specific secretions.

Properties of Na, K-ATPase from the salivary glands of the ixodid tick Amblyomma hebraeum

1980 ◽  
Vol 58 (6) ◽  
pp. 1052-1059 ◽  
Author(s):  
B. Rutti ◽  
B. Schlunegger ◽  
W. Kaufman ◽  
A. Aeschlimann
Keyword(s):  
Enzyme Activity ◽  
Salivary Glands ◽  
Fluid Secretion ◽  
Ixodid Tick ◽  
Rich Source ◽  
Amblyomma Hebraeum ◽  
Fundamental Properties ◽  
High Concentrations

Tick (Amblyomma hebraeum) salivary glands are a rich source of Na,K-ATPase (EC 3.6.1.3), the fundamental properties of which are similar to those of Na,K-ATPases from other sources. Inhibition of the enzyme by ouabain is quantitatively similar to the inhibition of fluid secretion by this drug. Harmaline at high concentrations also inhibited the Na,K-ATPase. The nucleotides GTP, ITP, and UTP were utilized as substrates, but all were less effective than ATP. Noradrenaline, dopamine, and phenoxybenzamine, all at concentrations known to influence fluid secretion in vitro, had no effect on enzyme activity.

scholarly journals Spatial aspects of Ca2+ signalling in pancreatic acinar cells

1993 ◽  
Vol 184 (1) ◽  
pp. 129-144
Author(s):  
P. Thorn
Keyword(s):  
Digestive Enzymes ◽  
Acinar Cells ◽  
Fluid Secretion ◽  
Cell Types ◽  
Cellular Mechanism ◽  
Pancreatic Acinar Cells ◽  
Secretory Cells ◽  
High Affinity ◽  
High Concentrations ◽  
Cell Changes

Secretory cells do not only respond to an agonist with a simple rise in [Ca2+]i. It is now clear that complex patterns of [Ca2+]i elevation in terms of space and time are observed in many cell types and that these patterns may be a cellular mechanism for the regulation of different responses. Ca2+ signalling in exocrine cells of the pancreas promotes the secretion of digestive enzymes and fluid. It has been shown that at high concentrations of agonist (acetylcholine or cholecystokinin) the [Ca2+]i response is initiated in the secretory pole of the cell before spreading across the whole cell. This site of initiation of the [Ca2+]i elevation is in the region where exocytotic release of enzymes occurs and is also the site of a Ca(2+)-dependent chloride channel thought to be crucially important for fluid secretion. Lower concentrations of agonist elicit [Ca2+]i oscillations with complex repetitive patterns characteristic of each agonist. At physiological agonist concentrations, we have recently described repetitive short-lasting Ca2+ spikes that are spatially restricted to the secretory pole of the cell. In addition to these spikes, cholecystokinin also promotes slow transient Ca2+ rises that result in a global rise in Ca2+. The inositol trisphosphate (InsP3) receptor plays a crucial role in all of these various agonist responses, most of which can be reproduced by the infusion of InsP3 into the cell. The high InsP3-sensitivity of the secretory pole is postulated to be due to a localization of high-affinity InsP3 receptors. We speculate that in response to cholecystokinin the short-lasting spikes elicit exocytosis from a small ‘available pool’ of vesicles and that the broader oscillations induce both exocytosis and cell changes that involve movement of vesicles into this ‘available pool’.

Suppression of carbachol-induced oscillatory Cl− secretion by forskolin in rat parotid and submandibular acinar cells

2008 ◽  
Vol 294 (3) ◽  
pp. G738-G747 ◽  
Author(s):  
Takahide Shintani ◽  
Chikara Hirono ◽  
Makoto Sugita ◽  
Yoshiko Iwasa ◽  
Yoshiki Shiba
Keyword(s):  
Membrane Potential ◽  
Salivary Glands ◽  
Acinar Cells ◽  
Fluid Secretion ◽  
Sympathetic Stimulation ◽  
Current Clamp ◽  
Inward Current ◽  
Parotid Acinar Cells ◽  
Current Clamp Mode ◽  
Rat Parotid

Sympathetic stimulation induces weak salivation compared with parasympathetic stimulation. To clarify this phenomenon in salivary glands, we investigated cAMP-induced modulation of Ca2+-activated Cl− secretion from rat parotid and submandibular acinar cells because fluid secretion from salivary glands depends on the Cl− secretion. Carbachol (Cch), a Ca2+-increasing agent, induced hyperpolarization of the cells with oscillatory depolarization in the current clamp mode of the gramicidin-perforated patch recording. In the voltage clamp mode at −80 mV, Cch induced a bumetanide-sensitive oscillatory inward current, which was larger in rat submandibular acinar cells than in parotid acinar cells. Forskolin and IBMX, cAMP-increasing agents, did not induce any marked current, but they evoked a small nonoscillatory inward current in the presence of Cch and suppressed the Cch-induced oscillatory inward current in all parotid acinar cells and half (56%) of submandibular acinar cells. In the current clamp mode, forskolin + IBMX evoked a small nonoscillatory depolarization in the presence of Cch and reduced the amplitude of Cch-induced oscillatory depolarization in both acinar cells. The oscillatory inward current estimated at the depolarized membrane potential was suppressed by forskolin + IBMX. These results indicate that cAMP suppresses Ca2+-activated oscillatory Cl− secretion of parotid and submandibular acinar cells at −80 mV and possibly at the membrane potential during Cch stimulation. The suppression may result in the weak salivation induced by sympathetic stimulation.

scholarly journals A fluid secretion pathway unmasked by acinar-specific Tmem16A gene ablation in the adult mouse salivary gland

2015 ◽  
Vol 112 (7) ◽  
pp. 2263-2268 ◽  
Author(s):  
Marcelo A. Catalán ◽  
Yusuke Kondo ◽  
Gaspar Peña-Munzenmayer ◽  
Yasna Jaramillo ◽  
Frances Liu ◽  
...  
Keyword(s):  
Salivary Glands ◽  
Time Course ◽  
Adult Mouse ◽  
Acinar Cells ◽  
Anion Channel ◽  
Fluid Secretion ◽  
Conditional Knockout ◽  
Channel Blockers ◽  
Secretion Pathway ◽  
Gene Ablation

Activation of an apical Ca2+-activated Cl− channel (CaCC) triggers the secretion of saliva. It was previously demonstrated that CaCC-mediated Cl− current and Cl− efflux are absent in the acinar cells of systemic Tmem16A (Tmem16A Cl− channel) null mice, but salivation was not assessed in fully developed glands because Tmem16A null mice die within a few days after birth. To test the role of Tmem16A in adult salivary glands, we generated conditional knockout mice lacking Tmem16A in acinar cells (Tmem16A−/−). Ca2+-dependent salivation was abolished in Tmem16A−/− mice, demonstrating that Tmem16A is obligatory for Ca2+-mediated fluid secretion. However, the amount of saliva secreted by Tmem16A−/− mice in response to the β-adrenergic receptor agonist isoproterenol (IPR) was comparable to that seen in controls, indicating that Tmem16A does not significantly contribute to cAMP-induced secretion. Furthermore, IPR-stimulated secretion was unaffected in mice lacking Cftr (Cftr∆F508/∆F508) or ClC-2 (Clcn2−/−) Cl− channels. The time course for activation of IPR-stimulated fluid secretion closely correlated with that of the IPR-induced cell volume increase, suggesting that acinar swelling may activate a volume-sensitive Cl− channel. Indeed, Cl− channel blockers abolished fluid secretion, indicating that Cl− channel activity is critical for IPR-stimulated secretion. These data suggest that β-adrenergic–induced, cAMP-dependent fluid secretion involves a volume-regulated anion channel. In summary, our results using acinar-specific Tmem16A−/− mice identify Tmem16A as the Cl− channel essential for muscarinic, Ca2+-dependent fluid secretion in adult mouse salivary glands.

scholarly journals Neurofibromin expression by normal salivary glands

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Eloá Borges Luna ◽  
Pâmella Pinho Montovani ◽  
Rafaela Elvira Rozza-de-Menezes ◽  
Karin Soares Cunha
Keyword(s):  
Salivary Gland ◽  
Salivary Glands ◽  
Acinar Cells ◽  
Staining Intensity ◽  
Neurofibromatosis 1 ◽  
Tissue Type ◽  
Sublingual Gland ◽  
Minor Salivary Glands ◽  
Expression Levels ◽  
Ductal Cells

AbstractIntroductionNeurofibromin, a protein encoded by theNF1gene, is mutated in neurofibromatosis 1, one of the most common genetic diseases. Oral manifestations are common and a high prevalence of hyposalivation was recently described in individuals with neurofibromatosis 1. Although neurofibromin is ubiquitously expressed, its expression levels vary depending on the tissue type and developmental stage of the organism. The role of neurofibromin in the development, morphology, and physiology of salivary glands is unknown and a detailed expression of neurofibromin in human normal salivary glands has never been investigated.AimTo investigate the expression levels and distribution of neurofibromin in acinar and ductal cells of major and minor salivary glands of adult individuals without NF1.Material and methodTen samples of morphologically normal major and minor salivary glands (three samples of each gland: parotid, submandibular and minor salivary; and one sample of sublingual gland) from individuals without neurofibromatosis 1 were selected to assess neurofibromin expression through immunohistochemistry. Immunoquantification was performed by a digital method.ResultsNeurofibromin was expressed in the cytoplasm of both serous and mucous acinar cells, as well as in ducts from all the samples of salivary glands. Staining intensity varied from mild to strong depending on the type of salivary gland and region (acini or ducts). Ducts had higher neurofibromin expression than acinar cells (p = 0.003). There was no statistical association between the expression of neurofibromin and the type of the salivary gland, considering acini (p = 0.09) or ducts (p = 0.50) of the four salivary glands (parotid, submandibular, minor salivary, and sublingual gland). Similar results were obtained comparing the acini (p = 0.35) and ducts (p = 0.50) of minor and major salivary glands. Besides, there was no correlation between the expression of neurofibromin and age (p = 0.08), and sex (p = 0.79) of the individuals, considering simultaneously the neurofibromin levels of acini and duct (n = 34).ConclusionNeurofibromin is expressed in the cytoplasm of serous and mucous acinar cells, and ductal cells of salivary glands, suggesting that this protein is important for salivary gland function.

scholarly journals Autoradiographic localization of dihydrotestosterone binding in the major salivary glands and other androgen-responsive organs of the mouse.

1987 ◽  
Vol 35 (10) ◽  
pp. 1053-1058 ◽  
Author(s):  
J I Morrell ◽  
E W Gresik ◽  
T Barka
Keyword(s):  
Growth Factor ◽  
Salivary Glands ◽  
Submandibular Gland ◽  
Cellular Localization ◽  
Incidental Finding ◽  
Acinar Cells ◽  
Unexpected Finding ◽  
Cervical Lymph Nodes ◽  
Major Salivary Glands ◽  
Duct Cells

Mouse submandibular glands show an androgen-dependent sexual dimorphism, reflected in higher concentrations in males than in females of bioactive peptides, such as epidermal growth factor (EGF), nerve growth factor, and renin in the cells of the granular convoluted tubules (GCT). Biochemical studies have demonstrated androgen receptors in submandibular gland and other androgen-responsive organs in mouse. We have determined the cellular localization of these receptors using steroid autoradiography. Fifteen adult gonadectomized male mice were injected intravenously with 0.13 microgram or 0.26 microgram [3H]-dihydrotestosterone (SA 135 Ci/mM); some animals were pre-treated with cyclocytidine to stimulate secretion by GCT cells. Animals were killed 15 min, 1, 2, or 3 hr after isotope injection. Steroid autoradiographs were prepared, and some were stained immunocytochemically for EGF. Of the different cell types of submandibular gland, the acinar cells most frequently and intensely concentrated [3H]-DHT; GCT cells also concentrated the hormone, as did a small number of striated duct cells. In the other major salivary glands, the only cells that concentrated the androgen were interlobular striated duct cells in sublingual gland. In prostate, anterior pituitary, and brain a large number of cells concentrated androgen, as has been previously reported. Androgen binding by the GCT cells was a predictable finding, since androgen-induced alterations in composition and form of these cells are well documented. The intense androgen concentration by the acinar cells was an unexpected finding and suggests a hitherto unknown androgen regulation of these cells. An incidental finding was intense concentration of [3H]-DHT in the nuclei of the endothelial cells of the post-capillary venules of the cervical lymph nodes.

Studies on the mechanism of fluid secretion by isolated salivary glands of Calliphora

1976 ◽  
Vol 64 (2) ◽  
pp. 311-322
Author(s):  
M. J. Berridge ◽  
B. D. Lindley ◽  
W. T. Prince
Keyword(s):  
Salivary Glands ◽  
Apical Membrane ◽  
Potassium Concentration ◽  
Basal Membrane ◽  
Fluid Secretion ◽  
Sodium Permeability ◽  
Bathing Medium ◽  
Major Cation ◽  
Diuretic Agent ◽  
External Potassium

1. Potassium is the major cation in the secretion of the salivary glands of Calliphora and is necessary for full secretory rates. 2. Other ions (rubidium and sodium) can support secretion in the absence of potassium. 39. During stimulation with 5-HT a Nernst plot of the basal membrane potential has a slope of 53 mV for a tenfold change in external potassium concentration and the slope at rest deviates from this over the range I-20 mM external potassium. 4. Hyperpolarization of the basal membrane by 5-HT is abolished if the chloride in the bathing medium is replaced by isethionate. 5. The diuretic agent amiloride inhibits fluid secretion by a mechanism which may include a reduction in calcium entry in addition to its recognized effect on sodium permeability. 6. A model is proposed in which fluid secretion is driven by the active transport of potassium across the apical membrane with chloride following passively.

scholarly journals Electrogenic NBCe1 (SLC4A4), but not electroneutral NBCn1 (SLC4A7), cotransporter undergoes cholinergic-stimulated endocytosis in salivary ParC5 cells

2008 ◽  
Vol 295 (5) ◽  
pp. C1385-C1398 ◽  
Author(s):  
Clint Perry ◽  
David O. Quissell ◽  
Mary E. Reyland ◽  
Irina I. Grichtchenko
Keyword(s):  
Membrane Trafficking ◽  
Basolateral Membrane ◽  
Fluorescent Microscopy ◽  
Acinar Cells ◽  
Fluid Secretion ◽  
Parotid Glands ◽  
Calmodulin Antagonist ◽  
Parotid Acinar Cells ◽  
Early Endosomes ◽  
Gf 109203X

Cholinergic agonists are major stimuli for fluid secretion in parotid acinar cells. Saliva bicarbonate is essential for maintaining oral health. Electrogenic and electroneutral Na+-HCO3− cotransporters (NBCe1 and NBCn1) are abundant in parotid glands. We previously reported that angiotensin regulates NBCe1 by endocytosis in Xenopus oocytes. Here, we studied cholinergic regulation of NBCe1 and NBCn1 membrane trafficking by confocal fluorescent microscopy and surface biotinylation in parotid epithelial cells. NBCe1 and NBCn1 colocalized with E-cadherin monoclonal antibody at the basolateral membrane (BLM) in polarized ParC5 cells. Inhibition of constitutive recycling with the carboxylic ionophore monensin or the calmodulin antagonist W-13 caused NBCe1 to accumulate in early endosomes with a parallel loss from the BLM, suggesting that NBCe1 is constitutively endocytosed. Carbachol and PMA likewise caused redistribution of NBCe1 from BLM to early endosomes. The PKC inhibitor, GF-109203X, blocked this redistribution, indicating a role for PKC. In contrast, BLM NBCn1 was not downregulated in parotid acinar cells treated with constitutive recycling inhibitors, cholinergic stimulators, or PMA. We likewise demonstrate striking differences in regulation of membrane trafficking of NBCe1 vs. NBCn1 in resting and stimulated cells. We speculate that endocytosis of NBCe1, which coincides with the transition to a steady-state phase of stimulated fluid secretion, could be a part of acinar cell adjustment to a continuous secretory response. Stable association of NBCn1 at the membrane may facilitate constitutive uptake of HCO3− across the BLM, thus supporting HCO3− luminal secretion and/or maintaining acid-base homeostasis in stimulated cells.

Regulation of electrolyte and fluid secretion in salivary acinar cells

1992 ◽  
Vol 263 (6) ◽  
pp. G823-G837 ◽  
Author(s):  
B. Nauntofte
Keyword(s):  
Ionic Composition ◽  
Basolateral Membrane ◽  
Acinar Cells ◽  
Fluid Secretion ◽  
Receptor Activation ◽  
Exchange Mechanism ◽  
Luminal Membrane ◽  
Net Uptake ◽  
Cl Channels ◽  
Simultaneous Activation

The primary secretion from exocrine gland cells is a fluid rich in Na+ and Cl- with a plasmalike ionic composition. Activation of specific receptors on the plasma membrane by hormones and neurotransmitters, which leads to activation of the phosphoinositol metabolism, results in release of Ca2+ from internal Ca2+ stores. Intracellular free Ca2+ concentration ([Ca2+]i) then rises simultaneously at both the basolateral and luminal parts of the acinar cell, reaching maximum values within 1 s after stimulation. In parotid acinar cells, increased [Ca2+]i activates the opening of maxi K+ channels located on the basolateral membrane and Cl- channels presumably located on the luminal membrane, resulting in rapid loss of K+ and Cl- and water and cell shrinkage. Extracellular electroneutrality is maintained by a paracellular Na+ flux into the lumen. Because of the simultaneous activation of K+ and Cl- channels, secretion occurs at a virtually constant membrane potential of about -60 mV. After maximal muscarinic cholinergic stimulation, loss of K+, Cl-, and water results in an approximate 25% reduction in cell volume within 10-15 s after receptor activation. Concomitant with loss of Cl-, there is a loss of HCO3- from the cell, causing a decrease in intracellular pH of 0.1 pH units because of the carbonic anhydrase-mediated conversion of CO2 into H+ and HCO3-. H+ generated from the metabolism and HCO3- production is compensated for by extrusion of H+ by a Na(+)-H+ exchange mechanism, which is responsible for approximately 75% of net Na+ gain that occurs after stimulation. Increased [Na+]i activates the Na(+)-K+ pump, which in turn extrudes Na+ from the cells. In both the unstimulated and stimulated states, cellular production of HCO3- can drive a net uptake of Cl- via the Cl(-)-HCO3- exchange mechanism operating in parallel with the Na(+)-H+ exchanger. The operation of the Cl(-)-HCO3- exchanger is, together with a Na(+)-K(+)-2Cl- cotransport system, essential for maintainance of a high [Cl-]i both in the unstimulated state and during Cl- reuptake.

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