Calcium-sensing receptor abrogates secretagogue- induced increases in intestinal net fluid secretion by enhancing cyclic nucleotide destruction
- John Geibel*,†,‡,
- Kumudesh Sritharan*,
- Rainer Geibel*,
- Peter Geibel*,
- J. Scott Persing*,
- Achim Seeger*,
- Torsten K. Roepke*,
- Markus Deichstetter§,
- Christian Prinz§,
- Sam X. Cheng*,
- David Martin¶, and
- Steven C. Hebert*,‡
- Departments of *Cellular and Molecular Physiology and
- †Surgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520;
- §Department of Medicine II, Technical University, Ismaningerstrasse 22, 81675 Munich, Germany; and
- ¶Department of Metabolic Disorders, Amgen, Inc., Thousand Oaks, CA 91320
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Contributed by Steven C. Hebert, April 12, 2006
Abstract
The calcium-sensing receptor (CaSR) provides a fundamental mechanism for diverse cells to detect and respond to modulations in the ionic and nutrient compositions of their extracellular milieu. The roles for this receptor are largely unknown in the intestinal tract, where epithelial cells are normally exposed to large variations in extracellular solutes. Here, we show that colonic CaSR signaling stimulates the degradation of cyclic nucleotides by phosphodiesterases and describe the ability of receptor activation to reverse the fluid and electrolyte secretory actions of cAMP- and cGMP-generating secretagogues, including cholera toxin and heat stable Escherichia coli enterotoxin STa. Our results suggest a paradigm for regulation of intestinal fluid transport where fine tuning is accomplished by the counterbalancing effects of solute activation of the CaSR on neuronal and hormonal secretagogue actions. The reversal of cholera toxin- and STa endotoxin-induced fluid secretion by a small-molecule CaSR agonist suggests that these compounds may provide a unique therapy for secretory diarrheas.
Footnotes
- ‡To whom correspondence may be addressed. E-mail: john.geibel{at}yale.edu or steven.hebert{at}yale.edu
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This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on May 3, 2005.
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Author contributions: J.G., S.X.C., D.M., and S.C.H. designed research; J.G., K.S., R.G., P.G., J.S.P., A.S., T.K.R., M.D., C.P., and S.X.C. performed research; D.M. contributed new reagents/analytic tools; J.G., T.K.R., C.P., S.X.C., and S.C.H. analyzed data; and J.G. and S.C.H. wrote the paper.
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Conflict of interest statement: S.C.H. is an inventor on patents covering CaSR active molecules, receives royalties on calcimimetics, and is a consultant on calcimimetics at Amgen, Inc. This work was supported in part by a gift from Amgen.
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See accompanying Profile on page 9387.
- Abbreviations:
- CaSR,
- calcium-sensing receptor;
- CTX,
- cholera toxin;
- STa,
- E. coli heat stable enterotoxin;
- PTH,
- parathyroid hormone;
- PDE,
- phosphodiesterases;
- IBMX,
- 3-isobutyl-1-methylxanthine;
- CFTR,
- cystic fibrosis transmembrane conductance regulator;
- NHE,
- sodium–hydrogen exchanger.
Abbreviations:
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Freely available online through the PNAS open access option.
- © 2006 by The National Academy of Sciences of the USA
