Type-1 Parathyroid Hormone (PTH)/PTH-Related Peptide (PTHrP) Receptors Activate Phospholipase C in Response to Carboxyl-Truncated Analogs of PTH(1–34)1
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...
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Published in | Endocrinology (Philadelphia) Vol. 139; no. 10; pp. 4293 - 4299 |
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Main Authors | , |
Format | Journal Article |
Language | English |
Published |
Endocrine Society
01.10.1998
|
Online Access | Get full text |
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Summary: | 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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ISSN: | 0013-7227 1945-7170 |
DOI: | 10.1210/endo.139.10.6261 |