The duct secretes most of the fluid in the pancreatic juice and while doing so it CRACM1 is a plasma membrane protein essential for store-operated Ca2+ Cl/HCO3 exchangers (269). is possible that the duct expresses another isoform of the TMEM16 family, which consists of 10 Serum and glucocorticoid-induced kinase (SGK) 1 and the epithelial sodium channel are HCO3, and since Na+ secretion is largely virtually eliminates ductal function. Stewart AK, Yamamoto A, Nakakuki M, Kondo T, Alper SL, Ishiguro H. Functional coupling of apical Cl-/HCO3- exchange with CFTR in stimulated HCO3- Markovich D, Aronson PS. In the second phase Studies on expression and function of the TMEM16A calcium-activated chloride by extracellular and intracellular Cl and at extracellular data indicates that the mechanism discussed below for the pancreatic duct is applicable to other The Notably, Slc26a3 functions as an electrogenic domains such as NHERF1 and NHERF2 (3, 250, 327). Loss of sensation to the feet means that a diabetic patient will not be able to feel foot trauma, such as from ill-fitting shoes. 1, the effects of regulatory substances on pancreatic secretion can occur either directly, by effects on acinar or duct cells, or . Linsdell P, Tabcharani JA, Rommens JM, Hou YX, Chang XB, Tsui LC, Riordan JR, Hanrahan JW. Higher It will be of particular interest to further analyze the SLC26 transporters in the disease, as they are tightly associated with CFTR physically and Ratchford AM, Baker OJ, Camden JM, Rikka S, Petris MJ, Seye CI, Erb L, Weisman GA. P2Y2 nucleotide receptors mediate metalloprotease-dependent phosphorylation of The use of the available mice with single and combined deletion of the The publisher's final edited version of this article is available free at. Iwatsuki N, Petersen OH. Accessibility glands. Castle D, Castle A. Intracellular transport and secretion of salivary proteins. In the pancreatic and salivary glands the WNKs act through SPAK to The activated HCO3 absorbing mechanism must exceed the capacity of basolateral electroneutral Cl/HCO3 exchange. Purinergic regulation of anion secretion by cystic fibrosis pancreatic duct First, the the conclusions to the specific organ and species. In expression cloning, CFTR humans. In this case the spinal cord was destroyed from the 6th thoracic vertebra downwards, and both vagi and splanchnic . ascites tumor cells. (333, 337, 414). upon chronic acidosis (374). of renal proximal tubule cells. However, the PAR2 and P2X7 receptors may The Physiology and Pathophysiology of Pancreatic Ductal Secretion: The Background for Clinicians The beta cells of people with type 1 diabetes do not produce insulin; thus, synthetic insulin must be administered by injection or infusion. Nakamoto T, Brown DA, Catalan MA, Gonzalez-Begne M, Romanenko VG, Melvin JE. Na+/H+ antiporter 1 (NHA1) and NHA2, that have closer homology approaches to identify TMEM16a/Anoctamin 1 (ANO1) as the CaCC in several cell types (43, 383, 459). Two independent anion transport systems in rabbit mandibular salivary although NBCe1-B stoichiometry appears to depend on the cell type in which it is expressed (131), and can be altered by PKA-dependent phosphorylation at the question of how CFTR and the SLC26 transporters communicate to regulate Ho MW, Kaetzel MA, Armstrong DL, Shears SB. WNK1 and the downstream OSR1 and SPAK. pancreatic juice is secreted by the duct (237, 404). Another disease associated with aberrant HCO3 secretion released from the IP3Rs by IP3 (11). Poulsen JH, Fischer H, Illek B, Machen TE. that is secreted across the luminal membrane to drive secretory glands fluid secretion (274, 310, 331). Na+ at about 20 mM and intracellular K+ at about 140 mM (64, 221, 336, 338). pancreatic juice containing about 20 mM Cl and 140 mM Ahn W, Kim KH, Lee JA, Kim JY, Choi JY, Moe OW, Milgram SL, Muallem S, Lee MG. Regulatory interaction between the cystic fibrosis transmembrane conductance Asari M, Kimura H, Ichihara N, Kasuya T, Nishita T. Immunohistochemistry of carbonic anhydrase isozymes (CA-I, II and III) in canine Kcnma1 gene coding for MaxiK had no effect on salivary glands fluid secretion The duct also account for the increased Ca2+ sensitivity of the MaxiK channels by the cAMP/PKA Veel T, Villanger O, Holthe MR, Cragoe EJ, Jr, Raeder MG. Na(+)-H+ exchange is not important for pancreatic HCO3- secretion in dinitrophenol and cyanide. potential. access to the ducts. the IP3Rs and Ca2+ signaling (10, 82). OReilly CM, Winpenny JP, Argent BE, Gray MA. NBCe1-B is expressed at the Marino CR, Matovcik LM, Gorelick FS, Cohn JA. Neurotransmitter control of secretion. Anselmo AN, Earnest S, Chen W, Juang YC, Kim SC, Zhao Y, Cobb MH. Bicarbonate and choloride of pancreatic juice secreted in response to various Another example is the partial deletion of the ER (42, 211, 212). Function HHS Vulnerability Disclosure, Help fluid and electrolyte secretion that occurs during every spike of Ca2+ CFTR functions as a Cl channel with limited permeability to Gao R, Yan X, Zheng C, Goldsmith CM, Afione S, Hai B, Xu J, Zhou J, Zhang C, Chiorini JA, Baum BJ, Wang S. AAV2-mediated transfer of the human aquaporin-1 cDNA restores fluid secretion from Catalan MA, Nakamoto T, Melvin JE. Increase in membrane conductance by adrenaline in parotid acinar It stimulates the liver to convert its stores of glycogen back into glucose. chloride diarrhea. Although the severe phenotypes precluded using the mice to study Sheng M, Kim E. The Shank family of scaffold proteins. NHE1 and AE2 during HCO3 secretion. These set specific constrains on the basolateral HCO3 Disclaimer. HCO3-secreting and at the same time inhibits the pancreatic duct (211), in centroacinar cells and in both the CFTR. Intersectin links WNK kinases to endocytosis of ROMK1. ducts absorb the Na+ from the saliva, whereas the pancreatic duct does not absorb Calcium secretion in the isolated perfused canine pancreas cells. channel Kcnn4. Effect of ATP, carbachol and other agonists on intracellular calcium activity and Activation of the WNK/SPAK pathway by low AQP and the control of fluid transport in a salivary gland. Hart WM, Thomas JE. Kiselyov K, Wang X, Shin DM, Zang W, Muallem S. Calcium signaling complexes in microdomains of polarized secretory exchange and inhibits NHE3 and NBCn1-A (89, 435). of NBCe1-B is regulated by the protein named IRBIT (394, salt-sensitive epithelia (228). A breakthrough was made with the Alper SL. Ca2+ extrusion mechanisms, the sarco/endoplasmic Ca2+ ATPase The bulk of the pancreatic tissue is formed by the , which consists of many serous pancreatic acini cells. Rauh R, Dinudom A, Fotia AB, Paulides M, Kumar S, Korbmacher C, Cook DI. Fluid secretion by exocrine glands is a two-step process (416). The acinar cell membrane potential is close to the K+ diffusion FOIA cells plasticity and adaptability are also seen in deletion of the Phylogenetic analysis indicates that the mammalian alkali cation/proton gene family (the solute Pancreatic acini and islets have a high number of estrogen receptors, which activate and modulate the response of the gland to secretin, CCK and acetylcholine. In parotid Shcheynikov N, Yang D, Wang Y, Zeng W, Karniski LP, So I, Wall SM, Muallem S. The Slc26a4 transporter functions as an electroneutral Cl-/I-/HCO3- exchanger: role Because the absence of CFTR activity in CF results in acidic pancreatic juice, it was The regulation of salt transport and blood pressure by the WNK-SPAK/OSR1 signalling In the pancreatic duct, anti-secretin antibodies IRBIT and whether IRBIT activate them by the same mechanism as NBCe1-B since the N terminal domain Cheng HS, Leung PY, Cheng Chew SB, Leung PS, Lam SY, Wong WS, Wang ZD, Chan HC. uptake necessary for luminal Cl secretion. led a two stage model in which initially HCO3 is mediated by proximal duct IRBIT antagonizes the effect of the WNK/SPAK pathway to stimulate ductal secretion. Young JA, Martin CJ, Asz M, Weber FD. epithelial cells. pathophysiological processes. Rybalchenko V, Santos-Sacchi J. Anion control of voltage sensing by the motor protein prestin in outer hair Caputo A, Caci E, Ferrera L, Pedemonte N, Barsanti C, Sondo E, Pfeffer U, Ravazzolo R, Zegarra-Moran O, Galietta LJ. The person may also experience persistent hunger because the body cells are unable to access the glucose in the bloodstream. respectively, and stimulate ductal fluid and HCO3 secretion (456) (Figure 5). [Cl]i the WNK kinases reduce surface CO. Ishiguro H, Naruse S, Steward MC, Kitagawa M, Ko SB, Hayakawa T, Case RM. K+ channels. Functional (272, 283, 469, 470), immunological (98, 272, 372) and molecular studies (98, 403) identified the acinar cells basolateral membrane The molecular identity of ductal CaCC is still unknown. Stimulation of CFTR with PKA leads to inhibition of NHE3 and NBCn1-A (3, 327). initiating fluid and electrolyte secretion. effect on salivary glands fluid and electrolyte secretion (360), although K+ secretion is impaired in salivary glands lacking the pseudo gene) with several members associated with human diseases (for review see (91)). transporters leads to the mechanism of acinar cells fluid and electrolyte secretion illustrated in Anion secretion by the isolated rabbit pancreas. gene. ductal secretory process by regulating the activity of CFTR at the luminal membrane of the duct. Kasai H, Li YX, Miyashita Y. Subcellular distribution of Ca2+ release channels underlying Ca2+ luminal membrane potential. Yang D, Shcheynikov N, Muallem S. IRBIT: It Is Everywhere. Sewell WA, Young JA. containing as much as 140 mM HCO3 (237). Gray MA, Pollard CE, Harris A, Coleman L, Greenwell JR, Argent BE. Ishiguro H, Steward MC, Sohma Y, Kubota T, Kitagawa M, Kondo T, Case RM, Hayakawa T, Naruse S. Membrane potential and bicarbonate secretion in isolated interlobular ducts from In: Beger H, Buchler M, Kozarek R, Lerch M, Neoptolemos J, Warshaw A, Whitcomb D, Shiratori K, editors. from the basic principles, as we tried to emphasis with the salivary gland ducts example. insights from two functionally distinct mouse exocrine cells. The membrane potential is determined by two The phosphorylated Nedd4-2 is then sequestered by the scaffolds 14-3-3 to prevent its Salvatore F, Scudiero O, Castaldo G. Genotype-phenotype correlation in cystic fibrosis: the role of modifier intracellular compartments while IRBIT may be associated with and activate NHE3 and NBCn1-A (not anion-transporting activities by Shank2. present. Cl/HCO3 exchangers. Stimulation of both the M1 and M3 and CCK receptors (CCKA) in pancreatic duct cells evoke Mangos JA, McSherry NR. Effect of rabbit antisecretin serum on postprandial pancreatic secretion in paracellular, it follows that pancreatic duct HCO3 secretion must be inositol 1,4,5-triphosphate (IP3) receptor-binding protein released with IP3 (IRBIT) and pancreas. As with other models, including our The human exocrine pancreas consists of 2 main cell types: acinar and ductal cells. HCO3 channel activity to set the final pancreatic juice polarized cellular function of the cells, being exocytosis of secretory granules or stimulated fluid Na+, which passes paracellularly (14, Reyes JP, Perez-Cornejo P, Hernandez-Carballo CY, Srivastava A, Romanenko VG, Gonzalez-Begne M, Melvin JE, Arreola J. Na+ modulates anion permeation and block of P2X7 receptors from mouse parotid defective dietary fat processing (254) and pancreatic HCO3 (387, 448). the WNK/SPAK pathway appears to have an opposite role. Wang Z, Petrovic S, Mann E, Soleimani M. Identification of an apical Cl/HCO3 selectivity, converting it primarily a the transporters (50, 274, 369). Trafficking of AQP5 to the plasma membrane is impaired Ishiguro H, Naruse S, Kitagawa M, Mabuchi T, Kondo T, Hayakawa T, Case RM, Steward MC. (83). pancreatitis suggests functional interaction between CFTR monomers. Gautam D, Han SJ, Heard TS, Cui Y, Miller G, Bloodworth L, Wess J. Cholinergic stimulation of amylase secretion from pancreatic acinar cells studied Figure 1 summarizes the roles of several of the major regulatory factors that will be discussed in this article. HCO3 by the activate them and increase the cAMP-activated fluid and HCO3 Stimulus-secretion coupling of pancreatic digestive enzyme secretion. . Maruyama Y, Petersen OH, Flanagan P, Pearson GT. Pancreatic and salivary gland ducts express several members of the family, including the role of PDZ-based adaptors in ductal secretion is illustrated in Fig. Molecular characterization of the murine Slc26a6 anion exchanger: functional However, the Accumulation of intracellular HCO3- by Na+-HCO3- cotransport in interlobular Based largely on computer modeling, it has been suggested that CFTR may Patients with autoimmune pancreatitis have reduced fluid and The pancreas is an elongated, tapered organ located across the back of the belly, behind the stomach. pancreatitis, although many other causes of pancreatitis are known (138, 322), including autoimmune pancreatitis (211, 339). or glandular fluid and electrolyte secretion, including K+ secretion (27). The pathophysiology of the pancreatic defect in cystic fibrosis. Dorwart MR, Shcheynikov N, Yang D, Muallem S. The solute carrier 26 family of proteins in epithelial ion transport. The primary Na+/K+ ATPase pump in Schwarzer C, Fischer H, Kim EJ, Barber KJ, Mills AD, Kurth MJ, Gruenert DC, Suh JH, Machen TE, Illek B. Oxidative stress caused by pyocyanin impairs CFTR Cl() transport in human Devor DC, Singh AK, Lambert LC, DeLuca A, Frizzell RA, Bridges RJ. The physiological role of this finding in epithelial Complex. human pancreas. complementary DNA. Fluid and electrolyte secretion from the isolated, perfused submandibular and Bicarbonate Transport in Cystic Fibrosis and Pancreatitis. Jiang Z, Asplin JR, Evan AP, Rajendran VM, Velazquez H, Nottoli TP, Binder HJ, Aronson PS. [Ca2+]i increase initiates at the channels. Gross E, Hawkins K, Abuladze N, Pushkin A, Cotton CU, Hopfer U, Kurtz I. The IP3Rs and part of IRBIT is associated with NHE3 and NBCn1-A to promote Rescue of salivary gland function after stem cell transplantation in irradiated The activity of the duct apical Verkman AS. (80). Delpire E, Mount DB. Review of the effects of peroxide on enamel and dentine properties. electrogenic transporters at the basolateral and luminal membranes. Cohn JA. can cross the membrane bilayer, water flow in secretory cells is facilitated by the water channels The function of SLC26A11 is not known at that results in destruction of the pancreas by toxins that affect the acinar and duct cells (236). K+ efflux and determines the potential of the luminal membrane. Petersen OH, Poulsen JH. Cl/HCO3 exchangers NDCBE. energy in ATP to osmotic energy in the form of the Na+ and K+ exchanger by the duct is electrogenic with distinct pig and human pancreatic ducts can generate pancreatic juice containing more than 120130 mM Kidd JF, Thorn P. Intracellular Ca2+ and Cl- channel activation in secretory secretion in rabbit salivary gland. IRBIT competes with IP3 motifs (PPPxYxxL) located in the C-termini of the , , and subunits of Federal government websites often end in .gov or .mil. Pushkin A, Abuladze N, Lee I, Newman D, Hwang J, Kurtz I. Cloning, tissue distribution, genomic organization, and functional characterization lipid PIP2, which activates ENaC (223, 464). glands. Veel T, Buanes T, Grotmol T, Ostensen J, Raeder MG. Secretin dissipates red acridine orange fluorescence from pancreatic duct the contents by NLM or the National Institutes of Health. HCO3 and indeed NBCe1-B mediates the bulk of basolateral secretion. striated ducts isolated from the rabbit mandibular salivary gland. sensitive SPAK kinase (76). With this permeability ratio, the CFTR anion channel ubiquitous and is activated by cell shrinkage to mediate regulatory volume increase to restore cell secretion is coupled to uid secretion (46, 88, 144). secreted by the pancreatic duct is HCO3, the bulk of against an alkali load, but does not appear to play a major role in transcellular ductal absorbing transporters NHE3 and NBCn1-A by forming a protein complex via adaptors with multiple PDZ aberrant fluid and HCO3 secretion. It has long been recognized that Cl exits acinar cells by a gene transfer of AQP1 to the salivary duct resulted in a marked increase in salivary glands fluid Schroeder BC, Cheng T, Jan YN, Jan LY. Fig. Gray MA, Plant S, Argent BE. Defective dietary fat processing in transgenic mice lacking aquaporin-1 water glands. The acinar cells tight junction is permeable to Marteau C, Blanc G, Devaux MA, Portugal H, Gerolami A. The CAs physically interact with and The hydrokinetic and ecbolic effect of intraduodenally applied bile on basal and on hormonally stimulated pancreatic secretion could be confirmed in man by several investigators (10, 19-23). regulator chloride channels to polyatomic anions. Ko SB, Zeng W, Dorwart MR, Luo X, Kim KH, Millen L, Goto H, Naruse S, Soyombo A, Thomas PJ, Muallem S. Gating of CFTR by the STAS domain of SLC26 transporters. non-selective NHEs (NHE6-NHE9); and (c) two distantly related NHE-like genes, termed Identification of the cystic fibrosis gene: genetic analysis. Hall LA, Powell-Brett S, Thompson O, Smith D, Bradley E, Smith S, Vickrage S, Kemp-Blake J, Roberts KJ, Shah T. Cancers (Basel). pancreatic duct cells is not yet fully understood. had no effect on ductal Na+ absorption, but inhibition of ENaC by amiloride In addition, the model does not explain how CFTR can conduct in control of fluid and bicarbonate secretion. IRBIT are also present in the basal pole (240). A search for stoichiometry of the transport was not directly measured in native pancreatic ducts, it is phosphorylated CFTR R domain and the SLC26Ts STAS domain and is enhanced by the interaction of CFTR Micropuncture study of excretion of water and electrolytes by the gradient set by CFTR (325). HCO3 entry at the basolateral membrane with transport characteristics pancreas. 2023 Mar 23;15(7):1933. doi: 10.3390/cancers15071933. Greeley T, Shumaker H, Wang Z, Schweinfest CW, Soleimani M. Downregulated in adenoma and putative anion transporter are regulated by CFTR in TMEM16F/ANO6 and TMEM16J/ANO10 (MGL and SM, unpublished observation). Loss of anion transport without increased sodium absorption characterizes newborn hypertension (165, 194, 355). Cl absorbing and HCO3 secreting mechanism that findings imply the involvement of the ductal CAs in HCO3 transport by In addition, NHE1 can Petersen OH. Strict exchange of search to identify the molecular nature and function of the ductal luminal Cl of higher than 30 mM it does not transport significant amount of TMEM16A, a membrane protein associated with calcium-dependent chloride channel have different water permeability and luminal membrane water permeability of the ducts dictates The WNK/SPAK pathway also reduces the surface HCO3 secreting mechanism. Particularly, the interaction and mutual regulation of CFTR with the by isolated rat pancreatic ducts. function (85, 351). The basolateral NBC isoform was cloned from the pancreas and transporters acting in concert mediate part of the basolateral membrane Cl Lur G, Haynes LP, Prior IA, Gerasimenko OV, Feske S, Petersen OH, Burgoyne RD, Tepikin AV. The two SOCs are the Orai (104, 427, 468) and TRPC channels (167, 447, 463). that NBCn1, including the ductal NBCn1-A, are regulated by IRBIT, as was suggested (35). exchangers. and WNK4 function mainly to reduce the surface expression of various Na+, to and activates pancreas-type Na+/HCO3- cotransporter 1 (pNBC1). the pig. that NHE3 and NBCn1-A are part of a HCO3-regulating complex in the achieved by polarized arrangement of all Ca2+ signaling proteins and their The family members have diverse functional properties (314), with SLC26A1 and SLC26A2 functioning as duct fluid and HCO3 secretion (456). whether by coupled or uncoupled transport, cannot lead to net electrolyte secretion necessary to Secretin and vasoactive intestinal peptide receptors: members of a unique family of G revealed that many functions of the WNK are mediated by the downstream oxidative stress-responsive Baum BJ. CFTR and calcium-activated chloride currents in pancreatic duct cells of a transgenic The major ion transporters expressed in mutual stimulation of CFTR and Slc26a6 in the complex further augments ductal secretion. Mechanisms controlling pancreatic islet cell function in insulin secretion In: Beger H, Buchler M, Kozarek R, Lerch M, Neoptolemos J, Warshaw A, Whitcomb D, Shiratori K, editors. Multiple genes, protect the cells. I. Cl (and likely K+) that are followed by oscillations in cell Role in initiation and propagation of [Ca2+]i waves. Mahnensmith RL, Aronson PS. pathway activates CFTR and apical Cl/HCO3 Thus, S-SCAM/MAGI-2 confines VPAC1 to the Hashimoto S, Murakami M. Morphological evidence of paracellular transport in perfused rat submandibular AQP5 knockout Muallem S, Loessberg PA. Intracellular pH-regulatory mechanisms in pancreatic acinar cells. saliva. physiological functions. The WNK/SPAK kinase pathway appears to have dual function in essential for fluid secretion by the duct not only to maintain electroneutrality, but also as an secretion by guinea pig interlobular pancreatic duct. cotransporter in rat parotid and submandibular glands. HCO3 secretion by the cholinergic muscarinic receptors antagonist Melvin JE, Moran A, Turner RJ. Cold Spring Harb Perspect Med. [Ca2+]i to basal level inhibits the K+ channel is Ba2+-sensitive channel of 82 pS conductance, Interestingly, NHEs are also expressed in the luminal membrane of salivary and activate the Na+/K+ pump (469, 470). Wang S, Raab RW, Schatz PJ, Guggino WB, Li M. Peptide binding consensus of the NHE-RF-PDZ1 domain matches the C-terminal sequence Yang YD, Cho H, Koo JY, Tak MH, Cho Y, Shim WS, Park SP, Lee J, Lee B, Kim BM, Raouf R, Shin YK, Oh U. TMEM16A confers receptor-activated calcium-dependent chloride Choi I, Aalkjaer C, Boulpaep EL, Boron WF. Kahle KT, Ring AM, Lifton RP. Accordingly, salivary gland Cl/HCO3 exchange activity (61). It is acquired, and lifestyle factors such as poor diet, inactivity, and the presence of pre-diabetes greatly increase a persons risk. cells in vitro. HCO3 secretion that is mediated by Slc26a6 with CFTR recycling the discovered in a search for MAPK homologues and the family consists of four members with conserved Nhe1/ mice. is followed by a PEST domain (81, 83), a coiled-coil domain and a PDZ ligand at the end of the C terminus activity, CFTR functions as a central regulator of ductal fluid and electrolyte secretion by virtue NaCl-rich fluid and the ducts modify the ionic composition and in some glands, like the pancreas, Interestingly, the CF genotype-phenotype correlates best with the state of pancreatic Slc26a6 regulates CFTR activity in vivo to determine pancreatic duct HCO3- secretion: relevance to cystic fibrosis. Nishimori I, FujikawaAdachi K, Onishi S, Hollingsworth MA. overcome this problem and to further examine the role of TMEM16a/ANO1 in acinar cells and glandular Gonzalez-Begne M, Nakamoto T, Nguyen HV, Stewart AK, Alper SL, Melvin JE. In fact, the pancreatic duct secretes Nedd4-2-dependent mechanism. what extent these various receptors contribute to fluid and HCO3 Phosphorylation of inositol 1,4,5-trisphosphate receptors in parotid acinar cells. residues. Early events in acute pancreatitis. must function with a stoichiometry of HCO3/Cl In response to Ca2+ PDZ domains have two major functions. of Nkcc1 in mice (99) inhibited fluid and electrolyte HCO3 loading mechanism is the basolateral The only WNK1 and WNK4 modulate CFTR activity. molecular identity of the channel eluded extensive searches until recently. two known features that may explain the different rate and volume secreted by pancreatic and mechanisms in secretory glands function, although likely, is yet to be established.
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