Document Detail


Increased receptor stimulation elicits differential calcium-sensing receptor(T888) dephosphorylation.
MedLine Citation:
PMID:  20233724     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The calcium-sensing receptor (CaR) elicits oscillatory Ca(2+)(i) mobilization associated with dynamic, inhibitory protein kinase C-mediated phosphorylation of CaR(T888). While modest CaR stimulation elicits Ca(2+)(i) oscillations, greater stimulation either increases oscillation frequency or elicits sustained responses by an unknown mechanism. Here, moderate CaR stimulation (2.5 mm Ca(2+)(o), 10 min) increased CaR(T888) phosphorylation (160-kDa mature receptor) 5-fold in CaR stably transfected HEK-293 cells, whereas 3-5 mm Ca(2+)(o) treatments were without apparent effect. Treatment with 2 mm Ca(2+)(o) caused sustained CaR(T888) phosphorylation (> or = 20 min) and oscillatory Ca(2+)(i) mobilization. However, 5 mm Ca(2+)(o) increased CaR(T888) phosphorylation only briefly while eliciting sustained Ca(2+)(i) mobilization, suggesting that greater CaR activation induces rapid CaR(T888) dephosphorylation, thus permitting sustained Ca(2+)(i) responses. Indeed, 5 mm Ca(2+)(o) stimulated protein phosphatase 2A activity and induced CaR(T888) dephosphorylation following acute phorbol ester pretreatment, the latter effect being mimicked by CaR-positive allosteric modulators (NPS-R467 and l-Phe). Finally, the phosphatase inhibitor calyculin-A reversed CaR-induced inhibition of parathyroid hormone secretion from bovine parathyroid slices and normal human parathyroid cells, demonstrating the physiological importance of phosphorylation status on parathyroid function. Therefore, high Ca(2+)(o)-stimulated protein kinase C acts in concert with high Ca(2+)(o)-induced phosphatase activity to generate and maintain CaR-induced Ca(2+)(i) oscillations via the dynamic phosphorylation and dephosphorylation of CaR(T888).
Authors:
Wanda D McCormick; Rebecca Atkinson-Dell; Katherine L Campion; Hee-Chang Mun; Arthur D Conigrave; Donald T Ward
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-03-16
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-03     Completed Date:  2010-06-11     Revised Date:  2011-07-28    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  14170-7     Citation Subset:  IM    
Affiliation:
Faculty of Life Sciences, The University of Manchester, Manchester M13 9NT, United Kingdom.
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MeSH Terms
Descriptor/Qualifier:
Animals
Calcium / metabolism*
Calcium Signaling
Cattle
Cells, Cultured
Humans
Immunoblotting
Kidney / cytology,  metabolism
Parathyroid Glands / metabolism*
Parathyroid Hormone / secretion*
Phosphorylation
Protein Kinase C / metabolism*
Protein Phosphatase 2 / metabolism
Receptors, Calcium-Sensing / metabolism*
Signal Transduction
Chemical
Reg. No./Substance:
0/Parathyroid Hormone; 0/Receptors, Calcium-Sensing; 7440-70-2/Calcium; EC 2.7.11.13/Protein Kinase C; EC 3.1.3.16/Protein Phosphatase 2
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