EFFECTS OF N-TERMINAL, MIDREGION, AND C-TERMINAL PARATHYROID HORMONE-RELATED PEPTIDES ON ADENOSINE-3',5'-MONOPHOSPHATE AND CYTOPLASMIC FREECALCIUM IN RAT AORTIC SMOOTH-MUSCLE CELLS AND UMR-106 OSTEOBLAST-LIKECELLS

N-Terminal analogs of PTH-related protein (PTHrP) and PTH bind to a co mmon receptor and exhibit similar biological properties. However, rece nt studies suggest that certain midregion and C-terminal PTHrP peptide s have activities distinct from those of PTH in the placenta and in os teoclasts, respectively. In this study we determined the biological ac tivities of full-length recombinant PTHrP-(1-141) and several syntheti c N-terminal, midregion, and C-terminal PTHrP fragments in two PTHrP-p roducing cell types. Peptides were tested for their ability to stimula te CAMP production and raise intracellular free calcium ([Ca2+]i) in p rimary rat aortic smooth muscle cells (VSMC) and UMR-106 rat osteoblas t-like (UMR) cells. In UMR cells PTHrP-(1-34)NH2, PTHrP-(1-141), and b ovine PTH-(1-34) all increased CAMP (approximately 50 fold) and [Ca2+] i (180 nm). By contrast, in VSMC, these N-terminal peptides increased CAMP (3-fold) but had no detectable effect on [Ca2+]i. PTHrP-(1-34) an d PTHrP-(1-141) significantly blunted the angiotensin 11-induced rise in CAMP (but not the calcium signal) consistent with the concept that PTHrP opposes angiotensin II activity in VSMC. PTHrP-(67-86)NH2, PTHrP -(107-138)NH2, and PTHrP-(107-111)NH2 had no effect on either CAMP or [Ca2+]i in either cell type. VSMC and UMR-106 cells both expressed a 2 .5-kilobase PTH/PTHrP receptor messenger RNA (MRNA) transcript. Howeve r, high affinity specific binding of I-125-labeled [Tyr36]PTHrP-(1-36) NH2 was detected in UMR cells but not in VSMC. We conclude that the PT H-like, N terminus of the PTHrP molecule is critical in induction of C AMP and [Ca2+]i pathways in UMR cells, and for CAMP stimulation in VSM C. In addition, PTHrP, like other established vasodilators, signals in VSMC mainly (if not exclusively) by increasing the production of CAMP .