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This version published online on February 3, 2005
Endocrinology, doi:10.1210/en.2004-1637
A more recent version of this article appeared on May 1, 2005
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Submitted on December 20, 2004
Accepted on January 26, 2005

The receptor for parathyroid hormone and parathyroid hormone-related peptide is hydrolyzed and its signaling properties are altered by directly binding the calpain small subunit

Masako Shimada, Matthew J. Mahon, Peter A. Greer, and Gino V. Segre*

Endocrine Unit, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; Queen's University Cancer Research Institute, Kingston, Ontario, Canada

* To whom correspondence should be addressed. E-mail: segre{at}helix.mgh.harvard.edu.

We show calcium-dependent, direct binding between the N terminal portion of the parathyroid hormone (PTH)/parathyroid hormone-related peptide receptor (PTH1R) C-terminal intracellular "tail" and the calpain small subunit. Binding requires, but may not be limited to, amino acids W474, S475, and W477. The wild-type full-length rPTH1R, but not rPTH1R with W474A/W477A substitutions, co-purifies with the endogenous calpain small subunit in HEK293 cells. Calpain hydrolyzes {Delta}Nt-rPTH1R, a receptor with a 156 amino acid N terminal deletion, in a calcium-dependent manner in vitro and in intact cells. Most importantly, PTH stimulation increases the cleavage of {Delta}Nt-rPTH1R and rPTH1R-yellow fluorescent protein (YFP) in HEK293 cells, and of talin in HEK293 cells expressing rPTH1R-YFP and in ROS17/2.8 osteoblast-like cells that express rPTH1R endogenously. The absence of calpain in Capn4-null embryonic fibroblasts and the lowered calpain activity in MC3T3-E1 osteoblastic cells due to stable expression of the calpain inhibitor, calpastatin, reduce PTH-stimulated cyclic AMP (cAMP) accumulation. The calpain small subunit is the second protein, in addition to the sodium-hydrogen exchanger regulatory factor (NHERF), and the first enzyme that binds the PTH1R; PTH1R bound to both of these proteins results in altered PTH signaling.
Key words: PTH/PTHrP receptor • The calpain small subunit • Protein interaction • Signaling




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