Parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHRP) regulate Na/H exchanger activity in osteoblastic cells, although the signaling components involved are not precisely defined. Since these peptide hormones can stimulate production of diverse second messengers (i.e. cAMP and diacylglycerol) that activate protein kinase A (PKA) and protein kinase C (PKC) in target cells, it is conceivable that either one or both of these pathways can participate in modulating exchanger activity. To discriminate among these possibilities, a series of synthetic PTH and PTHRP fragments were used that stimulate adenylate cyclase and/or PKC. In the osteoblastic cell line UMR-106, human PTH(1-34) and PTHRP(1-34) augmented adenylate cyclase activity, whereas PTH(3-34), PTH(28-42), and PTH(28-48) had no effect. Nevertheless, all these peptide fragments were found to enhance PKC translocation from the cytosol to the membrane in a dose-dependent (10 to 10M) manner. PTHRP(1-16), a biologically inert fragment, was incapable of influencing either the PKA or PKC pathway. PTH(1-34) and PTHRP(1-34), but not PTH(3-34), PTH(28-42), PTH(28-48), or PTHRP(1-16), elevated Na/H exchanger activity, implicating cAMP as the transducing signal. In accordance with this observation, forskolin (10 µM), which directly stimulates adenylate cyclase, also activated Na/H exchanger activity. The involvement of PKA was verified when the highly specific PKA inhibitor, H-89, completely abolished the stimulatory effect of PTH(1-34) and forskolin on Na/H exchange. In addition, Northern blot analysis revealed the presence of only the NHE-1 isoform of the Na/H exchanger in UMR-106 cells. In summary, these results indicated that PTH and PTHRP activate the Na/H exchanger NHE-1 isoform in osteoblastic UMR-106 cells exclusively via a cAMPdependent pathway.

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