Activation of the Calcium Sensing Receptor Decreases Secretagogue-Induced Fluid Secretion in the Rat Small Intestine
BackgroundThe calcium-sensing receptor (CaSR) has been localized and characterized in numerous tissues throughout the body. In the mammalian gastrointestinal tract, the CaSR is known to act as a nutrient sensor and has recently been found to play a role in intestinal fluid and electrolyte balance. T...
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Frontiers Media S.A.
2019-05-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphys.2019.00439/full |
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| author | Maria J. Barahona Renee M. Maina Taras Lysyy Michele Finotti Michele Finotti Giorgio Caturegli Vanessa Baratta Francesco D’Amico Francesco D’Amico David Mulligan John P. Geibel |
| author_facet | Maria J. Barahona Renee M. Maina Taras Lysyy Michele Finotti Michele Finotti Giorgio Caturegli Vanessa Baratta Francesco D’Amico Francesco D’Amico David Mulligan John P. Geibel |
| author_sort | Maria J. Barahona |
| collection | DOAJ |
| description | BackgroundThe calcium-sensing receptor (CaSR) has been localized and characterized in numerous tissues throughout the body. In the mammalian gastrointestinal tract, the CaSR is known to act as a nutrient sensor and has recently been found to play a role in intestinal fluid and electrolyte balance. This study aims to demonstrate the functionality of the CaSR as a modulator of fluid secretion and absorption along the small intestine.MethodsSmall intestine regions (proximal, middle, and distal) were isolated from Sprague Dawley rats and loaded into an ex vivo intestinal perfusion device that provides independent intraluminal and extraluminal (serosa/basolateral) perfusion. The regions were perfused with 5 and 7 mM of Ca2+, both in the presence and absence of forskolin (FSK), a potent secretagogue. Control experiments were conducted with intraluminal perfusate containing standard Ringer-HEPES buffer with a physiological concentration of Ca2+ (1 mM). A second set of comparison experiments was performed with intraluminal perfusates containing AC-265347, a CaSR activator and agonist, in the presence of FSK. In all experimental conditions, the intraluminal perfusate contained fluorescein isothiocyanate (FITC)-inulin, a nonabsorbable fluorescent marker of secretion and/or absorption. Intraluminal fluorescence signal was utilized as a measure of water movement at the start of the experiment and every 15 min for 90 min.ResultsUnder physiological conditions, increasing the concentration of Ca2+ in the luminal perfusate reduced intestinal fluid secretion in all regions. At a Ca2+ concentration of 7 mM, net fluid absorption was observed in all regions. In the presence of FSK, 5 mM Ca2+ significantly decreased fluid secretion and 7 mM Ca2+ abolished FSK-induced fluid secretion. Intraluminal perfusion with 5 mM Ca2+ was as effective as AC-265347, in reducing secretagogue-induced fluid hypersecretion in the proximal and middle regions.ConclusionThis study concludes that apical CaSR is active along the small intestine. Its activation by Ca2+ and/or calcimimetics reduces fluid secretion in a dose-dependent manner, with higher Ca2+ concentrations, or application of a calcimimetic, leading to fluid absorption. We furthermore show that, in the presence of FSK, receptor activation abates FSK secretagogue-induced fluid secretion. This presents a new therapeutic target to address secretory diarrheal illnesses. |
| first_indexed | 2024-12-13T08:38:38Z |
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| language | English |
| last_indexed | 2024-12-13T08:38:38Z |
| publishDate | 2019-05-01 |
| publisher | Frontiers Media S.A. |
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| spelling | doaj.art-6c18fdc5c9c24b36975b63c139e61b542022-12-21T23:53:35ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2019-05-011010.3389/fphys.2019.00439431275Activation of the Calcium Sensing Receptor Decreases Secretagogue-Induced Fluid Secretion in the Rat Small IntestineMaria J. Barahona0Renee M. Maina1Taras Lysyy2Michele Finotti3Michele Finotti4Giorgio Caturegli5Vanessa Baratta6Francesco D’Amico7Francesco D’Amico8David Mulligan9John P. Geibel10Department of Surgery, Yale School of Medicine, New Haven, CT, United StatesDepartment of Surgery, Yale School of Medicine, New Haven, CT, United StatesDepartment of Surgery, Yale School of Medicine, New Haven, CT, United StatesDepartment of Surgery, Yale School of Medicine, New Haven, CT, United StatesTransplantation and Hepatobiliary Surgery, University of Padua, Padua, ItalyDepartment of Surgery, Yale School of Medicine, New Haven, CT, United StatesDepartment of Surgery, Yale School of Medicine, New Haven, CT, United StatesDepartment of Surgery, Yale School of Medicine, New Haven, CT, United StatesTransplantation and Hepatobiliary Surgery, University of Padua, Padua, ItalyDepartment of Surgery, Yale School of Medicine, New Haven, CT, United StatesDepartment of Surgery, Yale School of Medicine, New Haven, CT, United StatesBackgroundThe calcium-sensing receptor (CaSR) has been localized and characterized in numerous tissues throughout the body. In the mammalian gastrointestinal tract, the CaSR is known to act as a nutrient sensor and has recently been found to play a role in intestinal fluid and electrolyte balance. This study aims to demonstrate the functionality of the CaSR as a modulator of fluid secretion and absorption along the small intestine.MethodsSmall intestine regions (proximal, middle, and distal) were isolated from Sprague Dawley rats and loaded into an ex vivo intestinal perfusion device that provides independent intraluminal and extraluminal (serosa/basolateral) perfusion. The regions were perfused with 5 and 7 mM of Ca2+, both in the presence and absence of forskolin (FSK), a potent secretagogue. Control experiments were conducted with intraluminal perfusate containing standard Ringer-HEPES buffer with a physiological concentration of Ca2+ (1 mM). A second set of comparison experiments was performed with intraluminal perfusates containing AC-265347, a CaSR activator and agonist, in the presence of FSK. In all experimental conditions, the intraluminal perfusate contained fluorescein isothiocyanate (FITC)-inulin, a nonabsorbable fluorescent marker of secretion and/or absorption. Intraluminal fluorescence signal was utilized as a measure of water movement at the start of the experiment and every 15 min for 90 min.ResultsUnder physiological conditions, increasing the concentration of Ca2+ in the luminal perfusate reduced intestinal fluid secretion in all regions. At a Ca2+ concentration of 7 mM, net fluid absorption was observed in all regions. In the presence of FSK, 5 mM Ca2+ significantly decreased fluid secretion and 7 mM Ca2+ abolished FSK-induced fluid secretion. Intraluminal perfusion with 5 mM Ca2+ was as effective as AC-265347, in reducing secretagogue-induced fluid hypersecretion in the proximal and middle regions.ConclusionThis study concludes that apical CaSR is active along the small intestine. Its activation by Ca2+ and/or calcimimetics reduces fluid secretion in a dose-dependent manner, with higher Ca2+ concentrations, or application of a calcimimetic, leading to fluid absorption. We furthermore show that, in the presence of FSK, receptor activation abates FSK secretagogue-induced fluid secretion. This presents a new therapeutic target to address secretory diarrheal illnesses.https://www.frontiersin.org/article/10.3389/fphys.2019.00439/fullCaSRFITC-inulinfluid homeostasisforskolingastrointestinal tract |
| spellingShingle | Maria J. Barahona Renee M. Maina Taras Lysyy Michele Finotti Michele Finotti Giorgio Caturegli Vanessa Baratta Francesco D’Amico Francesco D’Amico David Mulligan John P. Geibel Activation of the Calcium Sensing Receptor Decreases Secretagogue-Induced Fluid Secretion in the Rat Small Intestine Frontiers in Physiology CaSR FITC-inulin fluid homeostasis forskolin gastrointestinal tract |
| title | Activation of the Calcium Sensing Receptor Decreases Secretagogue-Induced Fluid Secretion in the Rat Small Intestine |
| title_full | Activation of the Calcium Sensing Receptor Decreases Secretagogue-Induced Fluid Secretion in the Rat Small Intestine |
| title_fullStr | Activation of the Calcium Sensing Receptor Decreases Secretagogue-Induced Fluid Secretion in the Rat Small Intestine |
| title_full_unstemmed | Activation of the Calcium Sensing Receptor Decreases Secretagogue-Induced Fluid Secretion in the Rat Small Intestine |
| title_short | Activation of the Calcium Sensing Receptor Decreases Secretagogue-Induced Fluid Secretion in the Rat Small Intestine |
| title_sort | activation of the calcium sensing receptor decreases secretagogue induced fluid secretion in the rat small intestine |
| topic | CaSR FITC-inulin fluid homeostasis forskolin gastrointestinal tract |
| url | https://www.frontiersin.org/article/10.3389/fphys.2019.00439/full |
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