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1. Mechanosensing Piezo channels in gastrointestinal disorders

Author

Swain, Sandip M. and Liddle, Rodger A.

Subjects
Ion channels -- Health aspects -- Physiological aspects, Pancreatic diseases -- Care and treatment -- Development and progression, Cellular signal transduction -- Research -- Health aspects -- Physiological aspects, Gastrointestinal diseases -- Care and treatment -- Development and progression, Health care industry
Abstract

All cells in the body are exposed to physical force in the form of tension, compression, gravity, shear stress, or pressure. Cells convert these mechanical cues into intracellular biochemical signals; this process is an inherent property of all cells and is essential for numerous cellular functions. A cell's ability to respond to force largely depends on the array of mechanical ion channels expressed on the cell surface. Altered mechanosensing impairs conscious senses, such as touch and hearing, and unconscious senses, like blood pressure regulation and gastrointestinal (GI) activity. The GI tract's ability to sense pressure changes and mechanical force is essential for regulating motility, but it also underlies pain originating in the GI tract. Recent identification of the mechanically activated ion channels Piezo1 and Piezo2 in the gut and the effects of abnormal ion channel regulation on cellular function indicate that these channels may play a pathogenic role in disease. Here, we discuss our current understanding of mechanically activated Piezo channels in the pathogenesis of pancreatic and GI diseases, including pancreatitis, diabetes mellitus, irritable bowel syndrome, GI tumors, and inflammatory bowel disease. We also describe how Piezo channels could be important targets for treating GI diseases., Introduction Mechanotransduction is essential for sensing touch, hearing, and autonomic functions such as blood pressure regulation, gastrointestinal (GI) motility, cell differentiation and development, muscle stretch, and vascular tone (1, 2). [...]

Published
2023
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5. Guanylyl cyclase C ameliorates visceral pain: an unsuspected link

Author

Liddle, Rodger A.

Subjects
Health care industry
Abstract

Visceral pain associated with irritable bowel syndrome afflicts 15% of the US population. Although treatments are limited, guanylyl cyclase C (GUCY2C) agonists alleviate pain and constipation. Until now, it was assumed that the activation of GUCY2C and production of cGMP in enterocytes stimulated fluid secretion and reduced visceral sensation. The recent discovery that a subtype of enteroendocrine cells (EECs) known as neuropod cells synapse with submucosal neurons unveiled a pathway for communicating gut signals to the nervous system. In this issue of the JCI, Barton et al. report that GUCY2C is enriched in neuropod cells and is involved with sensory nerve firing. Selective deletion of GUCY2C in mouse models suggests that defective GUCY2C neuropod-cell signaling underlies visceral pain. These studies introduce possibilities for dissociating the secretory and analgesic effects of GUCY2C agonism. Although further work remains, unveiling the role of neuropod cells is a major step in understanding visceral pain., Unexplained visceral pain It has been estimated that up to 50% of visits to a gastroenterologist are for evaluation and treatment of unexplained visceral pain, commonly referred to as irritable [...]

Published
2023
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9. TRPV4 channel opening mediates pressure-induced pancreatitis initiated by Piezo1 activation

Author

Swain, Sandip M., Romac, Joelle M.-J., Shahid, Rafiq A., Pandol, Stephen J., Liedtke, Wolfgang, Vigna, Steven R., and Liddle, Rodger A.

Subjects
Pancreatitis -- Physiological aspects, Trypsin -- Physiological aspects, Cell death -- Physiological aspects, Gallstones -- Physiological aspects, Genes, Surgery, Endoscopic retrograde cholangiopancreatography, Necrosis, Enzymes, Health care industry
Abstract

Elevated pressure in the pancreatic gland is the central cause of pancreatitis following abdominal trauma, surgery, endoscopic retrograde cholangiopancreatography, and gallstones. In the pancreas, excessive intracellular calcium causes mitochondrial dysfunction, premature zymogen activation, and necrosis, ultimately leading to pancreatitis. Although stimulation of the mechanically activated, calcium-permeable ion channel Piezo1 in the pancreatic acinar cell is the initial step in pressure-induced pancreatitis, activation of Piezo1 produces only transient elevation in intracellular calcium that is insufficient to cause pancreatitis. Therefore, how pressure produces a prolonged calcium elevation necessary to induce pancreatitis is unknown. We demonstrate that Piezo1 activation in pancreatic acinar cells caused a prolonged elevation in intracellular calcium levels, mitochondrial depolarization, intracellular trypsin activation, and cell death. Notably, these effects were dependent on the degree and duration of force applied to the cell. Low or transient force was insufficient to activate these pathological changes, whereas higher and prolonged application of force triggered sustained elevation in intracellular calcium, leading to enzyme activation and cell death. All of these pathological events were rescued in acinar cells treated with a Piezo1 antagonist and in acinar cells from mice with genetic deletion of Piezo1. We discovered that Piezo1 stimulation triggered transient receptor potential vanilloid subfamily 4 (TRPV4) channel opening, which was responsible for the sustained elevation in intracellular calcium that caused intracellular organelle dysfunction. Moreover, TRPV4 gene-KO mice were protected from Piezo1 agonist- and pressure-induced pancreatitis. These studies unveil a calcium signaling pathway in which a Piezo1-induced TRPV4 channel opening causes pancreatitis., Introduction The pancreas is highly sensitive to pressure (1-3), and elevated pancreatic duct pressure is a major cause of acute pancreatitis. A gallstone impacted at the junction of the pancreatic [...]

Published
2020
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19. Mechanism, assessment and management of pain in chronic pancreatitis: Recommendations of a multidisciplinary study group

Author

Anderson, Michelle A., Akshintala, Venkata, Albers, Kathryn M., Amann, Stephen T., Belfer, Inna, Brand, Randall, Chari, Suresh, Cote, Greg, Davis, Brian M., Frulloni, Luca, Gelrud, Andres, Guda, Nalini, Humar, Abhinav, Liddle, Rodger A., Slivka, Adam, Gupta, Rachelle Stopczynski, Szigethy, Eva, Talluri, Jyothsna, Wassef, Wahid, Wilcox, C. Mel, Windsor, John, Yadav, Dhiraj, and Whitcomb, David C.

Published
2016
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20. Chemical pancreatectomy: an unconventional approach to preventing autodigestion in pancreatitis

Author

Liddle, Rodger A.

Subjects
Abdominal pain -- Causes of -- Care and treatment, Pancreatectomy -- Methods, Pancreatitis -- Care and treatment -- Development and progression -- Complications and side effects, Acetic acid -- Usage, Health care industry
Abstract

Due to progressive inflammation, chronic pancreatitis destroys both the exocrine and endocrine pancreas and sensitizes pancreatic nerves, leading to unremitting pain. Unfortunately, there are no treatments for pancreatic inflammation and approaches to ameliorate pain are suboptimal. Pancreatic inflammation is particularly problematic because damage to acinar cells causes local release of digestive enzymes, which initiate pancreatic autodigestion. The combination of autodigestion and inflammation is unique to pancreatitis and undoubtedly contributes to the difficulty in devising effective treatments. In this issue of the JCI, Saleh et al. describe a nonsurgical technique to ablate pancreatic acinar cells, thus eliminating the source of digestive enzymes and preventing autodigestion. In mice and a nonhuman primate model, this approach effectively reduced inflammation and pain while preserving islet cell function. These findings support the concept that ongoing acinar cell damage is at the root of chronic pancreatitis and provide a possible strategy for clinical treatment., Chronic pancreatitis Picture yourself in a hospital room where your son has been admitted with pancreatitis. This is his third attack, and he is only 11 years old. You should [...]

Published
2021
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22. Contributors

Author

Akiba, Yasutada, primary, Al Alam, Denise, additional, Al-Sadi, Rana, additional, Aziz, Qasim, additional, Battaglioli, Eric J., additional, Bharucha, Adil E., additional, Blumberg, Richard S., additional, Bohin, Natacha, additional, Bornstein, Joel C., additional, Brierley, Stuart M., additional, Brookes, Simon J.H., additional, Castro, Joel, additional, Chang, Eugene B., additional, Chassaing, Benoit, additional, Cheung, Mary, additional, Ciorba, Matthew A., additional, Crowe, Sheila E., additional, Czerwinski, Michael, additional, Danopoulos, Soula, additional, Das, Soumita, additional, Dempsey, Peter J., additional, den Hartog, Gerco, additional, Enomoto, Hideki, additional, Erickson, Andelain, additional, Ernst, Peter B., additional, Farmer, Adam D., additional, Foong, Jaime P.P., additional, Frey, Mark R., additional, Gewirtz, Andrew T., additional, Ghishan, Fayez K., additional, Gribble, Fiona M., additional, Grundy, Luke, additional, Hao, Marlene M., additional, Harrington, Andrea M., additional, Hennig, Grant W., additional, Hu, Hongzhen, additional, Huizinga, Jan D., additional, Iyer, Shankar S., additional, Kaji, Izumi, additional, Kashyap, Purna C., additional, Kaunitz, Jonathan D., additional, Labus, Jennifer S., additional, Lavoie, Brigitte, additional, Liu, Cambrian Y., additional, Ma, Thomas Y., additional, Ma, Xiaoya, additional, Mawe, Gary M., additional, Merchant, Juanita L., additional, Messer, Jeannette S., additional, Miller, Larry, additional, Naliboff, Bruce D., additional, Nelson, Mark T., additional, Newgreen, Donald F., additional, Nighot, Prashant, additional, Passi, Monica, additional, Polk, D. Brent, additional, Pozo, Maria J., additional, Reimann, Frank, additional, Roberts, Geoffrey P., additional, Roland, Bani C., additional, Ruffle, James K., additional, Said, Hyder, additional, Samuelson, Linda C., additional, Schumacher, Michael A., additional, Shah, Yatrik M., additional, Shea-Donohue, Terez, additional, Shroyer, Noah F., additional, Spence, Jason R., additional, Spencer, Nick J., additional, Spohn, Stephanie N., additional, Stamp, Lincon A., additional, Stenson, William F., additional, Takaki, Miyako, additional, Tillisch, Kirsten, additional, Uesaka, Toshihiro, additional, van den Brink, Gijs R., additional, van Dop, Willemijn A., additional, Vegesna, Anil, additional, von Moltke, Jakob, additional, Wald, Arnold, additional, Westendorp, B. Florien, additional, Whitson, Mathew, additional, Wood, Jackie D., additional, Xu, Hua, additional, Yang, Vincent W., additional, Young, Heather M., additional, Young, Vincent B., additional, Abumrad, Nada A., additional, Alrefai, Waddah A., additional, Ammoury, Rana, additional, Anderson, Gregory J., additional, Asano, Shinji, additional, Bamias, Giorgos, additional, Bhutia, Yangzom D., additional, Blondet, Niviann M., additional, Borel, Patrick, additional, Cifarelli, Vincenza, additional, Collins, James F., additional, Cousins, Robert J., additional, Davidson, Nicholas O., additional, Dawson, Paul A., additional, de Lartigue, Guillaume, additional, Desmarchelier, Charles, additional, Dudeja, Pradeep K., additional, Flores, Shireen R.L., additional, Ganapathy, Vadivel, additional, Ghezzi, Chiara, additional, Gill, Ravinder K., additional, Gorelick, Fred S., additional, Grisham, Matthew B., additional, Harrison, Earl H., additional, Hecht, Gail A., additional, Israel, Dawn A., additional, Jamieson, James D., additional, Katona, Bryson W., additional, Kiela, Pawel R., additional, Kopec, Rachel E., additional, Kowdley, Kris V., additional, LaRusso, Nicholas F., additional, Lee, Seong M., additional, Liddle, Rodger A., additional, Liuzzi, Juan P., additional, Loo, Donald D.F., additional, Lynch, John P., additional, Masyuk, Anatoliy I., additional, Masyuk, Tatyana V., additional, Messner, Donald J., additional, Meyer, Mark B., additional, Murray, Karen F., additional, Nexo, Ebba, additional, Okamoto, Curtis T., additional, Ortega, Bernardo, additional, Pandol, Stephen, additional, Peek, Richard M., additional, Pike, J. Wesley, additional, Priyamvada, Shubha, additional, Proctor, Gordon B., additional, Rajendran, Vazhaikkurichi M., additional, Raybould, Helen E., additional, Rivera-Nieves, Jesus, additional, Said, Hamid M., additional, Sakai, Hideki, additional, Saksena, Seema, additional, Sala-Rabanal, Monica, additional, Schulzke, Jörg-Dieter, additional, Seidler, Ursula E., additional, Shaalan, Abeer K., additional, Sheikh, Irshad A., additional, Thiagarajah, Jay R., additional, Verkman, Alan S., additional, Wang, Xiaoyu, additional, Welling, Paul A., additional, Wolkoff, Allan W., additional, and Wright, Ernest M., additional

Published
2018
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26. Neuroepithelial circuit formed by innervation of sensory enteroendocrine cells

Author

Bohorquez, Diego V., Shahid, Rafiq A., Erdmann, Alan, Kreger, Alex M., Wang, Yu, Calakos, Nicole, Wang, Fan, and Liddle, Rodger A.

Subjects
Neural circuitry -- Physiological aspects, Gastrointestinal system -- Physiological aspects, Health care industry
Abstract

Satiety and other core physiological functions are modulated by sensory signals arising from the surface of the gut. Luminal nutrients and bacteria stimulate epithelial biosensors called enteroendocrine cells. Despite being electrically excitable, enteroendocrine cells are generally thought to communicate indirectly with nerves through hormone secretion and not through direct cell-nerve contact. However, we recently uncovered in intestinal enteroendocrine cells a cytoplasmic process that we named neuropod. Here, we determined that neuropods provide a direct connection between enteroendocrine cells and neurons innervating the small intestine and colon. Using cell-specific transgenic mice to study neural circuits, we found that enteroendocrine cells have the necessary elements for neurotransmission, including expression of genes that encode pre-, post-, and transsynaptic proteins. This neuroepithelial circuit was reconstituted in vitro by coculturing single enteroendocrine cells with sensory neurons. We used a monosynaptic rabies virus to define the circuit's functional connectivity in vivo and determined that delivery of this neurotropic virus into the colon lumen resulted in the infection of mucosal nerves through enteroendocrine cells. This neuroepithelial circuit can serve as both a sensory conduit for food and gut microbes to interact with the nervous system and a portal for viruses to enter the enteric and central nervous systems., Introduction Satiety, food preference, and even mood behaviors are a few of the functions modulated by gut chemosensation (1). Ingested nutrients and bacterial by-products contacting the gut epithelium stimulate enteroendocrine [...]

Published
2015
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27. Ildr1 gene deletion protects against diet-induced obesity and hyperglycemia

Author

Chandra, Rashmi, primary, Aryal, Dipendra K., additional, Douros, Jonathan D., additional, Shahid, Rafiq, additional, Davis, Supriya J., additional, Campbell, Jonathan E., additional, Ilkayeya, Olga, additional, White, Phillip J., additional, Rodriguez, Ramona, additional, Newgard, Christopher B., additional, Wetsel, William C., additional, and Liddle, Rodger A., additional

Published
2022
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38. Immunoglobulin-like domain containing receptor 1 mediates fat-stimulated cholecystokinin secretion

Author

Chandra, Rashmi, Wang, Yu, Shahid, Rafiq A., Vigna, Steven R., Freedman, Neil J., and Liddle, Rodger A.

Subjects
Cholecystokinin -- Health aspects, Blood lipoproteins -- Properties, Proteolipids -- Properties, Fatty acids -- Health aspects, Lipoproteins -- Properties, Cell receptors -- Properties, Health care industry
Abstract

Cholecystokinin (CCK) is a satiety hormone produced by discrete enteroendocrine cells scattered among absorptive cells of the small intestine. CCK is released into blood following a meal; however, the mechanisms [...]

Published
2013
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41. Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype

Author

Romac, Joelle M.J., Ohmuraya, Masaki, Bittner, Cathy, Majeed, M. Faraz, Vigna, Steven R., Que, Jianwen, Fee, Brian E., Wartmann, Thomas, Yamamura, Ken-ichi, and Liddle, Rodger A.

Subjects
Trypsin -- Research, Mice -- Research, Mice -- Genetic aspects, Trypsin inhibitors -- Research, Pancreatitis -- Genetic aspects, Pancreatitis -- Research, Biological sciences
Abstract

Endogenous trypsin inhibitors are synthesized, stored, and secreted by pancreatic acinar cells. It is believed that they play a protective role in the pancreas by inhibiting trypsin within the cell should trypsinogen become prematurely activated. Rodent trypsin inhibitors are highly homologous to human serine protease inhibitor Kazal-type 1 (SPINK1). The mouse has one pancreatic trypsin inhibitor known as SPINK3, and the rat has two trypsin inhibitors commonly known as pancreatic secretory trypsin inhibitors I and II (PSTI-I and -II). Rat PSTI-I is a 61-amino acid protein that shares 65% sequence identity with mouse SPINK3. It was recently demonstrated that mice with genetic deletion of the Spink3 gene ([Spink3.sup.-/-]) do not survive beyond 15 days and lack normal pancreata because of pancreatic autophagy. We have shown that targeted transgenic expression of the rat Psti1 gene to acinar cells in mice [TgN(Psti1)] protects mice against caerulein-induced pancreatitis. To determine whether the autophagic phenotype and lethality in [Spink3.sup.-/-] mice were due to lack of pancreatic trypsin inhibitor, we conducted breeding studies with [Spink.sup.3+/-] heterozygous mice and TgN(Psti1) mice. We observed that, whereas [Spink3.sup.+/+], [Spink3.sup.+/-], and [Spink3-/-]/TgN(Pstil) mice had similar survival rates, no [Spink3.sup.-/-] mice survived longer than 1 wk. The level of expression of SPINK3 protein in acini was reduced in heterozygote mice compared with wild-type mice. Furthermore, endogenous trypsin inhibitor capacity was reduced in the pancreas of heterozygote mice compared with wild-type or knockout mice rescued with the rat Psti1 gene. Surprisingly, the lesser amount of SPINK3 present in the pancreata of heterozygote mice did not predispose animals to increased susceptibility to caerulein-induced acute pancreatitis. We propose that a threshold level of expression is sufficient to protect against pancreatitis. doi: 10.1152/ajpgi.00431.2009 PSTI-I; pancreatitis; autophagy

Published
2010

42. Clinical features and physiological response to a test meal in purging disorder and bulimia nervosa

Author

Keel, Pamela K., Wolfe, Barbara E., Liddle, Rodger A., De Young, Kyle P., and Jimerson, David C.

Subjects
Bulimia -- Diagnosis, Bulimia -- Demographic aspects, Bulimia -- Physiological aspects, Bulimia -- Research, Cholecystokinin -- Physiological aspects, Cholecystokinin -- Dosage and administration, Cholecystokinin -- Research, Dinners and dining -- Methods, Dinners and dining -- Health aspects, Health, Psychology and mental health
Published
2007

45. Local disruption of the celiac ganglion inhibits substance P release and ameliorates caerulein-induced pancreatitis in rats

Author

Noble, Marc D., Romac, Joelle, Wang, Yu, Hsu, Jay, Humphrey, John E., and Liddle, Rodger A.

Subjects
Neurons -- Research, Endocytosis -- Research, Biological sciences
Abstract

Primary sensory neurons of the C and A[delta] subtypes express the vanilloid capsaicin receptor TRPV1 and contain proinflammatory peptides such as substance P (SP) that mediate neurogenic inflammation. Pancreatic injury stimulates these neurons causing the release of SP in the pancreas resulting in pancreatic edema and neutrophil infiltration that contributes to pancreatitis. Axons of primary sensory neurons innervating the pancreas course through the celiac ganglion. We hypothesized that disruption of the celiac ganglion by surgical excision or inhibition of C and A[delta] fibers through blockade of TRPV1 would reduce the severity of experimental pancreatitis by inhibiting neurogenic inflammation. Resiniferatoxin (RTX) is a specific TRPV1 agonist that, in high doses, selectively destroys C and A[delta] fibers. Sprague-Dawley rats underwent surgical ganglionectomy or application of 10 [micro]g RTX (vs. vehicle alone) to the celiac ganglion. One week later, pancreatitis was induced by six hourly intraperitoneal injections of caerulein (50 [micro]g/kg). The severity of pancreatitis was assessed by serum amylase, pancreatic edema, and pancreatic myeloperoxidase (MPO) activity. SP receptor (neurokinin-1 receptor, NK-1R) internalization in acinar cells, used as an index of endogenous SP release, was assessed by immunocytochemical quantification of NK-1R endocytosis. Caerulein administration caused significant increases in pancreatic edema, serum amylase, MPO activity, and NK-1R internalization. RTX treatment and ganglionectomy significantly reduced pancreatic edema by 46% (P < 0.001) and NK-1R internalization by 80% and 51% (P < 0.001 and P < 0.05, respectively). RTX administration also significantly reduced MPO activity by 47% (P < 0.05). Neither treatment affected serum amylase, consistent with a direct effect of caerulein. These results demonstrate that disruption of or local application of RTX to the celiac ganglion inhibits SP release in the pancreas and reduces the severity of acute secretagogue-induced pancreatitis. It is possible that selectively disrupting TRPV1-bearing neurons could be used to reduce pancreatitis severity. TRPV1; endocytosis; resiniferatoxin; neurogenic inflammation; neurokinin-1 receptor

Published
2006

47. Contributors

Author

Abraham, Clara, primary, Abreu, Maria T., additional, Akiba, Yasutada, additional, Anderson, James M., additional, Aziz, Qasim, additional, Baker, Kristi, additional, Baldwin, Graham S., additional, Barnard, John A., additional, Bharucha, Adil E., additional, Bitar, Khalil N., additional, Ashley Blackshaw, L., additional, Blumberg, Richard S., additional, Bommer, Guido T., additional, Bornstein, Joel C., additional, Brierley, Stuart M., additional, Brookes, Simon J.H., additional, Chao, Celia, additional, Cho, Judy, additional, Coen, Steven J., additional, Collins, James F., additional, Dempsey, Peter J., additional, Koh, Sang Don, additional, Englander, Ella W., additional, Enomoto, Hideki, additional, Fearon, Eric R., additional, Fiebiger, Edda, additional, Frey, Mark R., additional, Fukata, Masayuki, additional, Fukudo, Shin, additional, Furness, John B., additional, Ghishan, Fayez K., additional, Gillilland, Merritt G., additional, Gilmont, Robert R., additional, Gomez, Guillermo A., additional, Greeley, George H., additional, Gwynne, Rachel M., additional, Ham, Maggie, additional, Harrington, Andrea, additional, Hebbard, Geoffrey S., additional, Hellmich, Mark R., additional, Hermann, Gerlinda E., additional, Herness, Scott, additional, Hobson, Anthony R., additional, Holzer, Peter, additional, Horowitz, Michael, additional, Huffnagle, Gary B., additional, Hughes, Patrick, additional, Jadcherla, Sudarshan R., additional, Johansen, Finn-Eirik, additional, Johnson, Leonard R., additional, Katz, Jonathan P., additional, Kaunitz, Jonathan D., additional, Kuemmerle, John F., additional, Labus, Jennifer S., additional, Lavoie, Brigitte, additional, Lencer, Wayne I., additional, Linden, David R., additional, Ma, Thomas Y., additional, Massol, Ramiro, additional, Mawe, Gary M., additional, Mayer, Emeran A., additional, McHugh, Kirk M., additional, Merchant, Juanita L., additional, Mittal, Ravinder K., additional, Montrose, Marshall H., additional, Naliboff, Bruce D., additional, Nelson, Mark T., additional, Newgreen, Donald F., additional, Brent Polk, D., additional, Poole, Daniel P., additional, Pozo, Maria J., additional, Raghavan, Shreya, additional, Ray, Ramesh M., additional, Rayner, Christopher K., additional, Rogers, Richard C., additional, Rozengurt, Enrique, additional, Samuelson, Linda C., additional, Sanders, Kenton M., additional, Shaker, Reza, additional, Sjövall, Henrik, additional, Somara, Sita, additional, Szurszewski, Joseph H., additional, Tack, Jan, additional, Takeuchi, Koji, additional, Tetreault, Marie-Pier, additional, Tillisch, Kirsten, additional, Turner, Jerrold R., additional, van den Brink, Gijs R., additional, van Dop, Willemijn A., additional, VanDussen, Kelli L., additional, Wald, Arnold, additional, Ward, Sean M., additional, Wood, Jackie D., additional, Wright, Nicholas A., additional, Xu, Hua, additional, Yang, Vincent W., additional, Young, Heather M., additional, Young, Vincent B., additional, Abumrad, Nada A., additional, Alrefai, Waddah A., additional, Ambatipudi, Kiran S., additional, Ammoury, Rana F., additional, Anderson, Gregory J., additional, Argent, Barry E., additional, Borthakur, Alip, additional, Case, R.Maynard, additional, Catalán, Marcelo A., additional, Chen, Zhouji, additional, Cheng, Xiaodong, additional, Chepurny, Oleg G., additional, Cousins, Robert J., additional, Cuppoletti, John, additional, Davidson, Nicholas O., additional, Dawson, Paul A., additional, de Lartigue, Guillaume, additional, Dudeja, Pradeep K., additional, Forte, John G., additional, Ganapathy, Vadivel, additional, Gill, Ravinder K., additional, Gorelick, Fred S., additional, Granger, D.Neil, additional, Gray, Michael A., additional, Grisham, Matthew B., additional, Harrison, Earl H., additional, Hecht, Gail, additional, Hirayama, Bruce A., additional, Hodges, Kim, additional, Holt, George G., additional, Israel, Dawn A., additional, Jamieson, James D., additional, Karvar, Serhan, additional, Kevil, Christopher G., additional, Kiela, Pawel R., additional, Kowdley, Kris V., additional, LaRusso, Nicholas F., additional, Leech, Colin A., additional, Liddle, Rodger A., additional, Liu, Sumei, additional, Loo, Donald D.F., additional, Lynch, John P., additional, MacNaughton, Wallace K., additional, Malinowska, Danuta H., additional, Mansbach, Charles M., additional, Masyuk, Anatoliy I., additional, Masyuk, Tatyana V., additional, McKay, Derek M., additional, Melvin, James E., additional, Messner, Donald J., additional, Meyer, Mark B., additional, Murray, Karen F., additional, Nexo, Ebba, additional, Okamoto, Curtis, additional, Ortega, Bernardo, additional, Ouellette, André J., additional, Peek, Richard M., additional, Wesley Pike, J., additional, Raybould, Helen E., additional, Rustgi, Anil K., additional, Said, Hamid M., additional, Sala-Rabanal, Monica, additional, Schubert, Mitchell L., additional, Seidler, Ursula, additional, Sjöblom, Markus, additional, Söderholm, Johan D., additional, Steward, Martin C., additional, Thiagarajah, Jay R., additional, Verkman, A.S., additional, Welling, Paul A., additional, Williams, John A., additional, Wolkoff, Allan W., additional, Wright, Ernest M., additional, Yao, Xuebiao, additional, and Yule, David I., additional

Published
2012
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48. Identification of nonsulfated cholecystokinin-58 in canine intestinal extracts and its biological properties

Author

Reeve, Joseph R., Jr., Liddle, Rodger A., McVey, Douglas C., Vigna, Steven R., Solomon, Travis E., Keire, David A., Rosenquist, Grace, Shively, John E., Lee, Terry D., Chew, Peter, Green, Gary M., and Coskun, Tamer

Subjects
Gastric acid -- Research, Gallbladder -- Research, Biological sciences
Abstract

Nonsulfated CC[K.sub.58] [CC[K.sub.58](ns)] has not been considered to be of biological importance because CC[K.sub.58](ns) binds poorly to the CC[K.sub.A] receptor and has only been identified once in intestinal extracts. In this work, a radioimmunoassay specific for the COOH-terminal region of gastrin and CCK (antibody 5135) was used to monitor the purification of CCK molecular forms from canine intestinal extracts. A minor immunoreactive peak was associated with a major absorbance peak during an ion-exchange, HPLC step. Characterization of this minor immunoreactive peak demonstrated that it was CC[K.sub.58](ns). CC[K.sub.58](ns) is 14% as immunoreactive as sulfated CC[K.sub.8] [CC[K.sub.8](s)]. Amino acid analysis demonstrated that CC[K.sub.58](ns) was present at 50% the amount of CC[K.sub.58](s). In addition, we found that CC[K.sub.58](ns) does not potently displace an [sup.125]I-labeled CC[K.sub.10] analog from the CC[K.sub.A] receptor in mouse pancreatic membranes and does not stimulate amylase release from isolated pancreatic acini, or stimulate pancreatic secretion in an anesthetized rat model. By contrast, CC[K.sub.58](ns) does bind to CC[K.sub.B] receptors and stimulates gastric acid secretion via this receptor. The presence of CC[K.sub.58](ns) and its ability to selectively stimulate the CC[K.sub.B] receptor without stimulation of the CC[K.sub.A] receptor suggest that CC[K.sub.58](ns) may have unique physiological properties, especially tissues where the nonsultated peptide can act as a paracrine or neurocrine agent. gallbladder: pancreas; gastric acid; receptor binding; CC[K.sub.A]; CC[K.sub.B]

Published
2004

49. Calcineurin mediates pancreatic growth in protease inhibitor-treated mice

Author

Tashiro, Mitsuo, Samuelson, Linda C., Liddle, Rodger A., and Williams, John A.

Subjects
Calcineurin -- Research, Biological sciences
Abstract

CCK acts on pancreatic acinar cells to increase intracellular [Ca.sup.2+] leading to secretion of digestive enzymes and, in the long term, pancreatic growth. Calcineurin (CN) is a serine/ threonine-specific protein phosphatase activated by [Ca.sup.2+] and calmodulin that recently has been shown to participate in the growth regulation of cardiac and skeletal myocytes. We therefore tested the effect of two different CN inhibitors, cyclosporine A (CsA) and FK506, on mouse pancreatic growth induced by oral administration of the synthetic protease inhibitor camostat, a known stimulator of endogenous CCK release. Mice were fed a powdered diet with or without 0.1% camostat. Pancreatic wet weight, protein, and DNA were increased in response to camostat in a time-dependent manner over 10 days in ICR mice but not in CCK-deficient mice. Both CsA (15 mg/kg) and FK506 (3 mg/kg) given twice daily blocked the increase in pancreatic wet weight and protein and DNA content induced by camostat. The increase in plasma CCK induced by camostat was not blocked by CsA or FK506. Camostat feeding also increased the relative amount of CN protein, whereas levels of MAPKs, ERKs, and p38 were not altered. In summary, 1) CCK released by chronic camostat feeding induces pancreatic growth in mice; 2) this growth is blocked by treatment with both CsA and FK506, indicating a role for CN; 3) CCK stimulation also increases CN protein. In conclusion, activation and possibly upregulation of CN may participate in regulation of pancreatic growth by CCK in mice. cholecystokinin; camostat; FK506; cyclosporine A

Published
2004

50. Contributors

Author

Abrams, Julian A., primary, Afdhal, Nezam H., additional, Aggarwal, Rakesh, additional, Andersson, Karin L., additional, Andrews, Jane M., additional, Angulo, Paul, additional, Azpiroz, Fernando, additional, Bacon, Bruce R., additional, Baker, Christina Wood, additional, Balistreri, William F., additional, Baron, Todd H., additional, Barth, Bradley A., additional, Becker, Anne E., additional, Befeler, Alex S., additional, Ben-David, Kfir, additional, Blackshaw, L. Ashley, additional, Blechacz, Boris, additional, Brandt, Lawrence J., additional, Bray, George A., additional, Bresalier, Robert S., additional, Britton, Robert S., additional, Brookes, Simon J., additional, Buchman, Alan L., additional, Burdick, J. Steven, additional, Carithers, Robert L., additional, Champine, Julie G., additional, Chan, Francis K.L., additional, Cheatham, Joseph G., additional, Chitturi, Shivakumar, additional, Chung, Daniel C., additional, Chung, Raymond T., additional, Cima, Robert R., additional, Collins, Robert H., additional, Cook, Ian J., additional, Cox, Diane W., additional, Crowe, Sheila E., additional, Czaja, Albert J., additional, Czito, Brian G., additional, Das, Ananya, additional, Daum, Fredric, additional, Davis, Gary L., additional, Dawson, Paul A., additional, DeLegge, Mark H., additional, Demetri, George D., additional, DeVault, Kenneth R., additional, Di Bisceglie, Adrian M., additional, Dinning, Philip G., additional, Dotan, Iris, additional, Drossman, Douglas A., additional, Elliott, David E., additional, Elmunzer, B. Joseph, additional, Elta, Grace H., additional, Esposti, Silvia Degli, additional, Fallon, Michael B., additional, Farrell, Geoffrey C., additional, Farrell, James J., additional, Farrell, Richard J., additional, Feld, Jordan J., additional, Feldman, Mark, additional, Castillo, Carlos Fernández-del, additional, Ferreira, Lincoln E., additional, Feuerstadt, Paul, additional, Fontana, Robert J., additional, Forsmark, Chris E., additional, Fox, Jeffrey M., additional, Foxx-Orenstein, Amy E., additional, Friedenberg, Frank K., additional, Friedman, Lawrence S., additional, Gianella, Ralph A., additional, Ginsberg, Gregory G., additional, Glasgow, Robert E., additional, Gores, Gregory J., additional, Greenwald, David A., additional, Hammer, Heinz F., additional, Harford, William V., additional, Hass, David J., additional, Heathcote, E. Jenny, additional, Heldmann, Maureen, additional, Högenauer, Christoph, additional, Huston, Christopher D., additional, Itzkowitz, Steven H., additional, Jain, Rajeev, additional, Jensen, Dennis M., additional, Jensen, Robert T., additional, Jeyarajah, D. Rohan, additional, Jimenez, Ramon E., additional, Kahn, Ellen, additional, Kahrilas, Peter J., additional, Kamath, Patrick S., additional, Katzka, David A., additional, Kaunitz, Jonathan D., additional, Kelly, Ciarán P., additional, Khan, Seema, additional, Kim, Arthur Y., additional, Kimmey, Michael B., additional, Koch, Kenneth L., additional, Kowdley, Kris V., additional, Krawczynski, Krzysztof, additional, Kurtz, Robert C., additional, Lamont, J. Thomas, additional, Landis, Charles S., additional, Larson, Anne M., additional, Lau, James Y.W., additional, Lee, Edward L., additional, Lembo, Anthony J., additional, Leonis, Mike A., additional, Levitt, Michael D., additional, Lewis, James H., additional, Li, Hsiao C., additional, Lichtenstein, Gary R., additional, Liddle, Rodger A., additional, Lidofsky, Steven D., additional, Lindor, Keith D., additional, Loeser, Caroline, additional, Long, John D., additional, Lowe, Mark E., additional, Ludwig, Emmy, additional, Maiwald, Matthias, additional, Malagelada, Carolina, additional, Malagelada, Juan-R., additional, Marcello, Peter W., additional, Mark, Lawrence A., additional, Martin, Paul, additional, Mason, Joel B., additional, Matthews, Jeffrey B., additional, Mayer, Lloyd, additional, McClain, Craig J., additional, McDonald, George B., additional, Millham, Frederick H., additional, Minei, Joseph P., additional, Mirowski, Ginat W., additional, Misdraji, Joseph, additional, Morton, John, additional, Mulvihill, Sean J., additional, Nevah, Moises Ilan, additional, Norton, Jeffrey A., additional, Öberg, Kjell, additional, O’Leary, Jacqueline G., additional, O’Mahony, Seamus, additional, Orenstein, Susan R., additional, Orlando, Roy C., additional, Osterman, Mark T., additional, Pandol, Stephen J., additional, Pandolfino, John E., additional, Patil, Abhitabh, additional, Pemberton, John H., additional, Periyakoil, V.S., additional, Perrillo, Robert, additional, Peura, David A., additional, Pfau, Patrick R., additional, Podolsky, Daniel K., additional, Potak, Jonathan, additional, Pratt, Daniel S., additional, Proctor, Deborah Denise, additional, Ramakrishna, B.S., additional, Rao, Mrinalini C., additional, Rao, Satish S.C., additional, Reid, Andrea E., additional, Reinus, John F., additional, Relman, David A., additional, Richter, Joel E., additional, Roberts, Eve A., additional, Rosen, Hugo R., additional, Ross, Andrew S., additional, Roy-Chowdhury, Jayanta, additional, Roy-Chowdhury, Namita, additional, Runyon, Bruce A., additional, Russo, Michael A., additional, Sampson, Hugh A., additional, Sands, Bruce E., additional, Sarosi, George A., additional, Savides, Thomas J., additional, Schiller, Lawrence R., additional, Schubert, Mitchell L., additional, Sellin, Joseph H., additional, Semrin, M. Gaith, additional, Shah, Vijay H., additional, Shanahan, Fergus, additional, Siegel, Corey A., additional, Sjogren, Maria H., additional, Souza, Rhonda F., additional, Spechler, Stuart Jon, additional, Steinberg, William M., additional, Stevens, William E., additional, Stockland, Andrew H., additional, Stollman, Neil H., additional, Suchy, Frederick J., additional, Tack, Jan, additional, Talley, Nicholas J., additional, Tenner, Scott, additional, Teoh, Narci C., additional, Thiele, Dwain L., additional, Turnage, Richard H., additional, Ullman, Sonal P., additional, Vakil, Nimish, additional, Venkatasubramanian, Jayashree, additional, von Herbay, Axel, additional, Wald, Arnold, additional, Wang, David Q.-H., additional, Wang, Timothy C., additional, Whitcomb, David C., additional, Wilcox, C. Mel, additional, Willett, Christopher G., additional, Woodard, Gavitt, additional, Wyers, Stephan G., additional, and Yarze, Joseph C., additional

Published
2010
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