title: Influence of the amino-terminus on in vitro and in vivo biological activity of synthetic parathyroid hormone-like peptides of malignancy.
abstract: We compared the bioactivities of a synthetic truncated NH2-terminal fragment of the human (h) PTH-like peptide (PLP) associated with malignancies [hPLP-(3-34)], an intact NH2-terminal fragment [hPLP-(1-34)], and an NH2-terminal fragment of PTH [hPTH-(1-34)]. Although hPLP-(1-34) was less potent than hPTH-(1-34) in stimulating adenylate cyclase in rat renal membranes, hPLP-(1-34) and hPTH-(1-34) were equipotent in stimulating adenylate cyclase in OK renal cells as well as in UMR 108 osteosarcoma cells in vitro. In osteosarcoma cells, each of these peptides could desensitize adenylate cyclase responses to itself and to the other peptide, but could not reduce stimulation by prostaglandin E2. Renal membranes of vitamin D-deficient rats with secondary hyperparathyroidism had a reduced PLP-stimulated as well as PTH-stimulated adenylate cyclase response. The truncated analog hPLP-(3-34) was only a weak partial agonist and an antagonist in vitro, produced equivalent inhibition of hPLP-(1-34) and hPTH-(1-34) in renal and osseous cells, and could not desensitize agonist responses. In thyroparathyroidectomized rats in vivo, hPLP-(1-34) and hPTH-(1-34) increased cAMP excretion, enhanced phosphaturia, maintained plasma calcium, and reduced calciuria. Equimolar concentrations of hPLP-(3-34) produced no increases above control levels; however, high concentrations of this peptide mimicked PTH actions on renal and plasma ion handling while modestly augmenting cAMP excretion. These results demonstrate the importance of the first two residues of PLP for bioactivity, indicate that PLP and PTH interact at common receptor sites in vivo as well as in vitro, suggest that PLP may not be less potent than PTH in renal target cells, and indicate that the net result of interaction of these peptides with their common receptor in target tissues may reflect both activation and desensitization of receptor-mediated events.
authors.affiliation: Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: S A
authors.initials: SA
authors.lastname: Rabbani
authors.forename: J
authors.initials: J
authors.lastname: Mitchell
authors.forename: D R
authors.initials: DR
authors.lastname: Roy
authors.forename: G N
authors.initials: GN
authors.lastname: Hendy
authors.forename: D
authors.initials: D
authors.lastname: Goltzman
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001681:Biological Assay; D002118:Calcium / Q000097:blood / Q000652:urine; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D000242:Cyclic AMP / Q000652:urine; D015232:Dinoprostone / Q000494:pharmacology; D006801:Humans; D006961:Hyperparathyroidism / Q000201:enzymology / Q000209:etiology; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D009363:Neoplasm Proteins / Q000494:pharmacology*; D012516:Osteosarcoma / Q000201:enzymology; D010280:Parathyroid Glands / Q000502:physiology; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000494:pharmacology*; D010710:Phosphates / Q000652:urine; D051381:Rats; D013329:Structure-Activity Relationship; D013965:Thyroidectomy; D014407:Tumor Cells, Cultured; D014808:Vitamin D Deficiency / Q000150:complications / Q000201:enzymology
chemical_list: D009363:Neoplasm Proteins; C470121:PTHLH protein, human; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D010710:Phosphates; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D015232:Dinoprostone; D002118:Calcium