Calcium-sensing receptor-dependent activation of CREB phosphorylation in HEK293 cells and human parathyroid cells

Vimesh Ashvinkumar Avlani, Wenting Ma, Hee-chang Mun, Katherine Leach, Leigh Delbridge, Arthur Christopoulos, Arthur Conigrave

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In addition to its acute effects on hormone secretion, epithelial transport and shape change, the calcium-sensing receptor (CaSR) modulates the expression of genes that control cell survival, proliferation and differentiation, as well as the synthesis of peptide hormones and enzymes. In the present study, we investigated the impacts of a CaSR agonist and several CaSR modulators on phosphorylation of transcription factor CREB residue S133 in CaSR-expressing HEK-293 cells (HEK-CaSR) cells and human adenomatous parathyroid cells. Elevated Ca2+o concentration had no effect on CREB phosphorylation (p-CREB) in control HEK-293 cells but stimulated p-CREB in both HEK-CaSR cells and human parathyroid cells. In addition, p-CREB was stimulated by the positive modulator cinacalcet and inhibited by the negative modulator NPS 2143 in both CaSR-expressing cell types. Two positive modulators that bind in the receptor s Venus FlyTrap (VFT) domain, L-phenylalanine (L-Phe) and S-methylglutathione (SMG) had no effect on p-CREB in HEK-CaSR cells demonstrating the existence of pronounced signalling bias. Analysis of the signaling pathways using specific inhibitors demonstrated that PI-PLC and conventional protein kinase C (PKC) isoforms make major contributions to Ca2+o-induced p-CREB in both cell-types, suggesting key roles for Gq/11. In addition, in parathyroid cells but not HEK-CaSR cells, activation of p-CREB was dependent on Gi/o, demonstrating the existence of cell-type specific signalling.
Original languageEnglish
Pages (from-to)1097 - 1104
Number of pages8
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number10
Publication statusPublished - 2013

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