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J. Biol. Chem., Vol. 277, Issue 52, 50543-50549, December 27, 2002
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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.
Protein Kinase C (PKC) Phosphorylation of the
Ca2+o-sensing Receptor (CaR) Modulates
Functional Interaction of G Proteins with the CaR
Cytoplasmic Tail*
*
This work was supported by the National Institutes of
Health Grant DK54934 (to M. B.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Endocrine-Hypertension
Div., Brigham and Women's Hospital, 221 Longwood Ave., Boston, MA
02115. Tel.: 617-732-5694; Fax: 617-732-5764.
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