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Am J Physiol Endocrinol Metab 295: E665-E671, 2008. First published June 24, 2008; doi:10.1152/ajpendo.00036.2008
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Eliminating phosphorylation sites of the parathyroid hormone receptor type 1 differentially affects stimulation of phospholipase C and receptor internalization

Susanne U. Miedlich1 and Abdul B. Abou-Samra2

1Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and 2Wayne State University School of Medicine, Detroit, Michigan

Submitted 19 January 2008 ; accepted in final form 19 June 2008

The parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor (PTH1R) belongs to family B of seven-transmembrane-spanning receptors and is activated by PTH and PTHrP. Upon PTH stimulation, the rat PTH1R becomes phosphorylated at seven serine residues. Elimination of all PTH1R phosphorylation sites results in prolonged cAMP accumulation and impaired internalization in stably transfected LLC-PK1 cells. The present study explores the role of individual PTH1R phosphorylation sites in PTH1R signaling through phospholipase C, agonist-dependent receptor internalization, and regulation by G protein-coupled receptor kinases. By means of transiently transfected COS-7 cells, we demonstrate that the phosphorylation-deficient (pd) PTH1R confers dramatically enhanced coupling to Gq/11 proteins upon PTH stimulation predominantly caused by elimination of Ser491/492/493, Ser501, or Ser504. Reportedly, impaired internalization of the pd PTH1R, however, is not dependent on a specific phosphorylation site. In addition, we show that G protein-coupled receptor kinase 2 interferes with pd PTH1R signaling to Gq/11 proteins at least partially by direct binding to Gq/11 proteins.

G protein-coupled receptor kinases; phosphorylation


Address for reprint requests and other correspondence: S. U. Miedlich, Endocrine Unit, Massachusetts General Hospital/Harvard Medical School, Thier 1101, 50 Blossom St., Boston, MA 02114 (e-mail: smiedlich{at}partners.org)






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