Obligate mitogen-activated protein kinase activation in parathyroid hormone stimulation of calcium transport but not calcium signaling

PTH regulates calcium homeostasis through direct actions on its cognate typ e I receptor in the kidney and bone. PTH inhibits phosphate transport in re nal proximal (PCT) tubules and stimulates calcium absorption by distal conv oluted tubules (DCT). We examined PTH activation of the mitogen-activated p rotein kinase (MAPK) cascade raf-MEK-ERK in PCT and DCT cells and its effec ts on calcium transport and signaling. In DCT cells, PTH stimulates phospho rylation of ERK2 and activation of ERK2 kinase and is blocked by the MEK in hibitor PD98059. In DCT cells, stimulation of calcium entry with ionomycin did not activate ERK2 or augment PTH-stimulated ERK2 activity, indicating t hat MAPK activation lies upstream of calcium entry. ERK2 activation by PTH was blocked by the protein kinase C inhibitor calphostin-C but was unaffect ed by the protein kinase A inhibitor Rp-cAMPs. PD98059 abolished the increa se of intracellular calcium induced by PTH demonstrating that ERK2 activati on is directly involved in the increase of intracellular calcium activated by PTH in the DCT. Thus, PTH- stimulated ERK2 activation is PKC dependent a nd calcium independent. PTH also induced ERK2 phosphorylation in PCT cells. However, this effect is not involved in the transient rise of intracellula r calcium because PD98059 did not inhibit the PTH-stimulated rise of intrac ellular calcium but abolished ERK2 activation. In conclusion, PTH activates MAPK in both distal and proximal renal tubule cells. However, the rise of [Ca2+](i) depends upon MAPK activation only in distal cells. Thus, a common PTH1R exhibits differential signaling along the nephron that contributes t o the ability to regulate distinct physiological actions of PTH.