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Type-1 Parathyroid Hormone (PTH)/PTH-Related Peptide (PTHrP) Receptors Activate Phospholipase C in Response to Carboxyl-Truncated Analogs of PTH(1–34)¹

Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: F. Richard Bringhurst, M.D., Endocrine Unit, Wellman 5, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: bringhurst.richard{at}mgh.harvard.edu

The carboxyl(C)-truncated human (h) PTH (hPTH) analog hPTH(1–31), which activates adenylyl cyclase (AC), but not protein kinase C, in rat osteosarcoma cells, exerts an anabolic effect on rat bone in vivo similar to that of hPTH(1–34). It has been proposed, therefore, that this action of PTH(1–34) is mediated exclusively by stimulation of AC via the rat type-1 PTH/PTH-related peptide (PTHrP) receptor (PTH1R).

To determine whether this selective signaling pattern also might be a property of the hPTH1R, we studied signal transduction via heterologously expressed hPTH1Rs in response to activation by hPTH(1–34), hPTH(1–31), and a C-truncated analog that does not increase rat bone mass in vivo, hPTH(1–30). In porcine LLC-PK1 cells that stably expressed recombinant hPTH1Rs, these three peptides activated AC identically (EC₅₀ = 1–2 nM). In cells with comparable expression of rat PTH1Rs, AC activation by hPTH(1–34) and hPTH(1–31) again was identical, whereas full activation by hPTH(1–30) required higher concentrations (EC₅₀ = 10 nM vs. 1 nM). Surprisingly, hPTH(1–31) fully stimulated phospholipase C (PLC), via both species of PTH1Rs, with potency that was similar (hPTH1Rs) or slightly reduced (rat PTH1Rs), relative to that of hPTH(1–34). hPTH(1–30), however, was 5-fold less potent than hPTH(1–34) in activating PLC via hPTH1Rs and showed weak and only partial activity via the rat PTH1R. Comparable results were obtained when human and rat PTH1Rs were transiently expressed heterologously in COS-7 cells or homologously in HEK 293 and UMR 106–01 cells, respectively. Binding affinities of these C-truncated peptides to human and rat PTH1Rs were concordant with their relative potencies in activating PLC.

We conclude that hPTH(1–31) and, to a lesser extent, hPTH(1–30) can activate PLC, as well as AC, via both rat and human PTH1Rs. Accordingly, a role for PLC activation in the anabolic action of PTH in vivo cannot be excluded.

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