Effects of N-terminal, midregion, and C-terminal parathyroid hormone-related peptides on adenosine 3',5'-monophosphate and cytoplasmic free calcium in rat aortic smooth muscle cells and UMR-106 osteoblast-like cells.

Abstract

N-Terminal analogs of PTH-related protein (PTHrP) and PTH bind to a common receptor and exhibit similar biological properties. However, recent studies suggest that certain midregion and C-terminal PTHrP peptides have activities distinct from those of PTH in the placenta and in osteoclasts, respectively. In this study we determined the biological activities of full-length recombinant PTHrP-(1-141) and several synthetic N-terminal, midregion, and C-terminal PTHrP fragments in two PTHrP-producing cell types. Peptides were tested for their ability to stimulate cAMP production and raise intracellular free calcium ([Ca2+]i) in primary rat aortic smooth muscle cells (VSMC) and UMR-106 rat osteoblast-like (UMR) cells. In UMR cells PTHrP-(1-34)NH2, PTHrP-(1-141), and bovine 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) and PTHrP-(1-141) significantly blunted the angiotensin II-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. However, high affinity specific binding of 125I-labeled [Tyr36] PTHrP-(1-36)NH2 was detected in UMR cells but not in VSMC. We conclude that the PTH-like, N terminus of the PTHrP molecule is critical in induction of cAMP and [Ca2+]i pathways in UMR cells, and for cAMP stimulation in VSMC. In addition, PTHrP, like other established vasodilators, signals in VSMC mainly (if not exclusively) by increasing the production of cAMP.

Possible Role of Parathyroid Hormone–Related Protein as a Proinflammatory Cytokine in Atherosclerosis

“…20 We showed herein that PKA inhibitors as well as PTHrP(7-34), which lacks cAMPinducing activity, 21 blocked the effect of PTHrP(1-36) on MCP-1 overexpression in VSMC. In this regard, MCP-1 upregulation by leptin in aortic endothelial cells has recently been reported to depend on PKA activition.…”

“…Since this peptide can stimulate cAMP in VSMC, 20 we initially tested the effect of protein kinase A (PKA) inhibitors. Both RpcAMPS and H89, at 5ϫ10 Ϫ5 and 10 Ϫ7 mol/L, respectively, prevented the PTHrP-induced MCP-1 gene expression at 6 hours in these cells (Figure 4).…”

Role of the Renin-Angiotensin System on the Parathyroid Hormone–Related Protein Overexpression Induced by Nephrotoxic Acute Renal Failure in the Rat

“…These findings further support the notion that PTHrP upregulation might be related to the mechanisms associated with Ang II-induced kidney injury. It was suggested previously that, in the arterial wall, PTHrP might act locally to antagonize some of the effects of Ang II on vascular smooth muscle cells (4,17,37). Thus, although further work is needed to define the true pathogenetic role of both proteins in ARF, PTHrP might either exert a reciprocal control on or recapitulate at least some Ang II effects in the acutely damaged kidney.…”

Na/H Exchanger Regulatory Factors Control Parathyroid Hormone Receptor Signaling by Facilitating Differential Activation of Gα Protein Subunits

“…In some cases, occupancy of the PTHR activates only one signaling pathway. For example, in vascular smooth muscle cells, PTH stimulates adenylyl cyclase but not PLC (3,4), whereas in keratinocytes (5,6), cardiac myocytes (7,8), and lymphocytes (9 -11), the PTHR activates PLC but not adenylyl cyclase. In osteoblasts and kidney tubule cells, PTH activates both adenylyl cyclase and PLC (12)(13)(14).…”