Acid-base transport in pancreas—new challenges

Novak, Ivana; Haanes, Kristian Agmund; Wang, Jing

doi:10.3389/fphys.2013.00380

Cited by 32 publications

(40 citation statements)

References 113 publications

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“…Pancreatic acini secrete enzyme-rich fluid which may be potentially acidic, although this is not fully settled [16,40]. Pancreatic ducts are exposed to acinar fluid, and they themselves can be stimulated to produce of HCO 3 − -rich fluid with pH~8.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, there are hydrolytic enzymes released into pancreatic juice, exosomal NTPDase1/CD39 and ecto-5′-nucleotidase/CD73 [13,14], and it may be questionable whether the more distal ducts would be exposed to sufficient acinar ATP for P2 receptor activation. Pancreatic ducts are not just passive conduits for enzyme secretion, but they produce HCO 3 − -rich fluid that is essential for normal pancreatic function and digestion [15,16].…”

Section: Introductionmentioning

confidence: 99%

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ATP release, generation and hydrolysis in exocrine pancreatic duct cells

Kowal

Yegutkin

Novak

2015

Purinergic Signalling

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Extracellular adenosine triphosphate (ATP) regulates pancreatic duct function via P2Y and P2X receptors. It is well known that ATP is released from upstream pancreatic acinar cells. The ATP homeostasis in pancreatic ducts, which secrete bicarbonate-rich fluid, has not yet been examined. First, our aim was to reveal whether pancreatic duct cells release ATP locally and whether they enzymatically modify extracellular nucleotides/sides. Second, we wished to explore which physiological and pathophysiological factors may be important in these processes. Using a human pancreatic duct cell line, Capan-1, and online luminescence measurement, we detected fast ATP release in response to pH changes, bile acid, mechanical stress and hypo-osmotic stress. ATP release following hypo-osmotic stress was sensitive to drugs affecting exocytosis, pannexin-1, connexins, maxi-anion channels and transient receptor potential cation channel subfamily V member 4 (TRPV4) channels, and corresponding transcripts were expressed in duct cells. Direct stimulation of intracellular Ca(2+) and cAMP signalling and ethanol application had negligible effects on ATP release. The released ATP was sequentially dephosphorylated through ecto-nucleoside triphosphate diphosphohydrolase (NTPDase2) and ecto-5'-nucleotidase/CD73 reactions, with respective generation of adenosine diphosphate (ADP) and adenosine and their maintenance in the extracellular medium at basal levels. In addition, Capan-1 cells express counteracting adenylate kinase (AK1) and nucleoside diphosphate kinase (NDPK) enzymes (NME1, 2), which contribute to metabolism and regeneration of extracellular ATP and other nucleotides (ADP, uridine diphosphate (UDP) and uridine triphosphate (UTP)). In conclusion, we illustrate a complex regulation of extracellular purine homeostasis in a pancreatic duct cell model involving: ATP release by several mechanisms and subsequent nucleotide breakdown and ATP regeneration via counteracting nucleotide-inactivating and nucleotide-phosphorylating ecto-enzymes. We suggest that extracellular ATP homeostasis in pancreatic ducts may be important in pancreas physiology and potentially in pancreas pathophysiology.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ATP release, generation and hydrolysis in exocrine pancreatic duct cells

Kowal

Yegutkin

Novak

2015

Purinergic Signalling

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“…The physiological role of CaCC (e.g., ANO1) in pancreatic ducts is in mediating secretion [25, 45]. One of the interesting questions is how overexpression of this channel could regulate other cellular functions in PDAC.…”

Section: Discussionmentioning

confidence: 99%

ANO1 (TMEM16A) in pancreatic ductal adenocarcinoma (PDAC)

Sauter

Novak

Pedersen

et al. 2014

Pflugers Arch - Eur J Physiol

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Pancreatic ductal adenocarcinoma (PDAC) has one of the worst survival rates of all cancers. ANO1 (TMEM16A) is a recently identified Ca2+-activated Cl− channel (CaCC) that is upregulated in several tumors. Although ANO1 was subject to extensive studies in the recent years, its pathophysiological function has only been poorly understood. The aim of the present study is to establish the significance of ANO1 in PDAC behavior and demarcate its roles in PDAC from those of the volume-regulated anion channel (VRAC). We performed qPCR and Western blot measurements on different PDAC cell lines (Panc-1, Mia PaCa 2, Capan-1, AsPC-1, BxPC-3) and compared the results to those obtained in a human pancreatic ductal epithelium (HPDE) cell line. All cancer cell lines showed an upregulation of ANO1 on mRNA and protein levels. Whole-cell patch-clamp recordings identified large Ca2+ and voltage-dependent Cl− currents in PDAC cells. Using siRNA knockdown of ANO1 and three ANO1 inhibitors (T16Ainh-A01, CaCCinh-A01, and NS3728), we found that ANO1 is the main constituent of CaCC current in PDAC cells. We further characterized these three inhibitors and found that they had unspecific effects on the free intracellular calcium concentration. Functional studies on PDAC behavior showed that surprisingly inhibition of ANO1 did not influence cellular proliferation. On the other hand, we found ANO1 channel to be pivotal in PDAC cell migration as assessed in wound healing experiments.Electronic supplementary materialThe online version of this article (doi:10.1007/s00424-014-1598-8) contains supplementary material, which is available to authorized users.

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“…In terms of functional roles, the acinar cells secrete a small volume of an NaCl-rich secretion plus many types of digestive enzymes (8–20 g per day) in an inactive form, together with various factors (e.g., ATP) that contribute to cell signalling within the ductal system [118]. Acinar cells secrete in response to stimulation by acetylcholine, cholecystokinin (CCK), and several other agonists.…”

Section: Role Of Cftr In the Exocrine Pancreasmentioning

confidence: 99%

Role of CFTR in epithelial physiology

Saint‐Criq

Gray

2016

Cell. Mol. Life Sci.

306

291

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Salt and fluid absorption and secretion are two processes that are fundamental to epithelial function and whole body fluid homeostasis, and as such are tightly regulated in epithelial tissues. The CFTR anion channel plays a major role in regulating both secretion and absorption in a diverse range of epithelial tissues, including the airways, the GI and reproductive tracts, sweat and salivary glands. It is not surprising then that defects in CFTR function are linked to disease, including life-threatening secretory diarrhoeas, such as cholera, as well as the inherited disease, cystic fibrosis (CF), one of the most common life-limiting genetic diseases in Caucasian populations. More recently, CFTR dysfunction has also been implicated in the pathogenesis of acute pancreatitis, chronic obstructive pulmonary disease (COPD), and the hyper-responsiveness in asthma, underscoring its fundamental role in whole body health and disease. CFTR regulates many mechanisms in epithelial physiology, such as maintaining epithelial surface hydration and regulating luminal pH. Indeed, recent studies have identified luminal pH as an important arbiter of epithelial barrier function and innate defence, particularly in the airways and GI tract. In this chapter, we will illustrate the different operational roles of CFTR in epithelial function by describing its characteristics in three different tissues: the airways, the pancreas, and the sweat gland.

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Acid-base transport in pancreas—new challenges

Cited by 32 publications

References 113 publications

ATP release, generation and hydrolysis in exocrine pancreatic duct cells

ATP release, generation and hydrolysis in exocrine pancreatic duct cells

ANO1 (TMEM16A) in pancreatic ductal adenocarcinoma (PDAC)

Role of CFTR in epithelial physiology

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