The N-terminal portion of parathyroid hormone-related protein mediates the inhibition of apical Na⁺/H⁺ exchange in opossum kidney cells

Parathyroid hormone (PTH) and PTH-related protein (PTHrP) can activate a common receptor in several different cell types. Both PTH and N-terminal PTHrP peptides have been shown to acutely inhibit the apical Na⁺/H⁺ exchanger in the renal proximal tubule. In this study, the ability of various PTHrP fragments to inhibit apical Na⁺/H⁺ exchange was investigated. In addition, the signal transduction events associated with PTHrP inhibition of apical Na⁺/H⁺ exchange in polarized OK-P cells were characterized. Both PTHrP-(134)NH₂ and recombinant full-length PTHrP-(1-141) inhibited apical Na⁺/H⁺ exchange activity by approximately 50%. These changes occurred in close temporal association with significant (threefold) increases in cellular cAMP accumulation. PTHrP-(1-34)NH₂ had no effect on intracellular Ca²⁺, inositol phosphate production, or protein kinase C activity. PTHrP peptides, including PTHrP-(38-64)NH₂, PTHrP-(6786)NH₂, PTHrP-(102-107)NH₂, and PTHrP-(107-139)NH₂, which lack the PTH-like N terminus, had no effect on the antiporter activity or cAMP accumulation. The results demonstrate that the N- terminal portion of the PTHrP molecule is responsible for inhibition of the apical Na⁺/H⁺ antiporter in OK-P cells.