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J. Biol. Chem., Vol. 277, Issue 52, 50543-50549, December 27, 2002

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Protein Kinase C (PKC) Phosphorylation of the Ca²⁺_o-sensing Receptor (CaR) Modulates Functional Interaction of G Proteins with the CaR Cytoplasmic Tail^*

Yong-Feng Jiang, Zaixiang Zhang, Olga Kifor, Charles R. Lane, Stephen J. Quinn, and Mei Bai

From the Endocrine-Hypertension Division, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115

The extracellular calcium (Ca²⁺_o)-sensing receptor (CaR) activates Ca²⁺ influx independent of the release of intracellular Ca²⁺ stores. The latter can be negatively regulated by protein kinase C (PKC) through phosphorylation of Thr-888 of the CaR. In this study, we substituted Thr-888 with various amino acid residues or a stop codon to understand how PKC phosphorylation of the CaR inhibits receptor-mediated release of intracellular Ca²⁺ stores. Substitutions of Thr-888 with hydrophobic and hydrophilic amino acid residues had various effects on CaR-mediated release of intracellular Ca²⁺ stores as well as activation of Ca²⁺ influx. Several point mutations, such as T888D, had marked negative effects on CaR-mediated release of intracellular Ca²⁺ stores but not on phorbol myristate acetate-insensitive activation of Ca²⁺ influx. Presumably, the negatively charged aspartate mimics phospho-threonine. Interestingly, truncating the receptor at 888 had an even more pronounced negative effect on CaR-elicited release of intracellular Ca²⁺ stores without significantly affecting CaR-mediated activation of Ca²⁺ influx. Therefore, truncation at position 888 of the CaR affects the activity of the receptor in a manner that resembles PKC phosphorylation of the CaR. This in turn suggests that PKC phosphorylation of the CaR prevents G protein subtypes from interacting with the region of the receptor critical for releasing Ca²⁺ stores, which is missing in the truncated receptor.

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