Document Detail


Calcium-sensing receptor is a physiologic multimodal chemosensor regulating gastric G-cell growth and gastrin secretion.
MedLine Citation:
PMID:  20876097     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The calcium-sensing receptor (CaR) is the major sensor and regulator of extracellular Ca(2+), whose activity is allosterically regulated by amino acids and pH. Recently, CaR has been identified in the stomach and intestinal tract, where it has been proposed to function in a non-Ca(2+) homeostatic capacity. Luminal nutrients, such as Ca(2+) and amino acids, have been recognized for decades as potent stimulants for gastrin and acid secretion, although the molecular basis for their recognition remains unknown. The expression of CaR on gastrin-secreting G cells in the stomach and their shared activation by Ca(2+), amino acids, and elevated pH suggest that CaR may function as the elusive physiologic sensor regulating gastrin and acid secretion. The genetic and pharmacologic studies presented here comparing CaR-null mice and wild-type littermates support this hypothesis. Gavage of Ca(2+), peptone, phenylalanine, Hepes buffer (pH 7.4), and CaR-specific calcimimetic, cinacalcet, stimulated gastrin and acid secretion, whereas the calcilytic, NPS 2143, inhibited secretion only in the wild-type mouse. Consistent with known growth and developmental functions of CaR, G-cell number was progressively reduced between 30 and 90 d of age by more than 65% in CaR-null mice. These studies of nutrient-regulated G-cell gastrin secretion and growth provide definitive evidence that CaR functions as a physiologically relevant multimodal sensor. Medicinals targeting diseases of Ca(2+) homeostasis should be reviewed for effects outside traditional Ca(2+)-regulating tissues in view of the broader distribution and function of CaR.
Authors:
Jianying Feng; Clark D Petersen; David H Coy; Jian-Kang Jiang; Craig J Thomas; Martin R Pollak; Stephen A Wank
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural     Date:  2010-09-27
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  107     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-13     Completed Date:  2010-11-22     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  17791-6     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Bombesin / analogs & derivatives,  pharmacology
Calcium Signaling / physiology*
Cell Proliferation
Gastrin-Secreting Cells / drug effects,  physiology,  secretion*
Gastrins / secretion*
Homeostasis / physiology*
Hydrogen-Ion Concentration
Immunohistochemistry
Mice
Microscopy, Fluorescence
Naphthalenes / pharmacology
Peptide Fragments / pharmacology
Receptors, Calcium-Sensing / antagonists & inhibitors,  genetics,  metabolism,  physiology*
Grant Support
ID/Acronym/Agency:
P01 DK070756/DK/NIDDK NIH HHS; P01 DK070756-040002/DK/NIDDK NIH HHS; P01-0707056//PHS HHS
Chemical
Reg. No./Substance:
0/BIM 26226; 0/Gastrins; 0/N-(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine; 0/Naphthalenes; 0/Peptide Fragments; 0/Receptors, Calcium-Sensing; PX9AZU7QPK/Bombesin
Comments/Corrections

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