Calcium-sensing receptor abrogates secretagogue- induced increases in intestinal net fluid secretion by enhancing cyclic nucleotide destruction.
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.
Geibel
John
J
Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA. john.geibel@yale.edu
Sritharan
Kumudesh
K
Geibel
Rainer
R
Geibel
Peter
P
Persing
J Scott
JS
Seeger
Achim
A
Roepke
Torsten K
TK
Deichstetter
Markus
M
Prinz
Christian
C
Cheng
Sam X
SX
Martin
David
D
Hebert
Steven C
SC
D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002413:Cations, Divalent / Q000737:chemistry; D007419:Intestinal Secretions / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009712:Nucleotides, Cyclic / Q000378:metabolism*; D010627:Phenethylamines; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011437:Propylamines; D051381:Rats; D044169:Receptors, Calcium-Sensing / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000814:Aniline Compounds; D001427:Bacterial Toxins; D002413:Cations, Divalent; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D009712:Nucleotides, Cyclic; D010627:Phenethylamines; D011437:Propylamines; D044169:Receptors, Calcium-Sensing; D010727:Phosphoric Diester Hydrolases; D010738:Type C Phospholipases; D002118:Calcium