| Increased receptor stimulation elicits differential calcium-sensing receptor(T888) dephosphorylation. | |
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MedLine Citation:
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PMID: 20233724 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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). |
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Authors:
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Wanda D McCormick; Rebecca Atkinson-Dell; Katherine L Campion; Hee-Chang Mun; Arthur D Conigrave; Donald T Ward |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-03-16 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 285 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-05-03 Completed Date: 2010-06-11 Revised Date: 2011-07-28 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 14170-7 Citation Subset: IM |
Affiliation:
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Faculty of Life Sciences, The University of Manchester, Manchester M13 9NT, United Kingdom. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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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:
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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 |
| Comments/Corrections | |
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