Parathyroid hormone (PTH) leads to the inhibition of Na-P_i cotransport activity and to the downregulation of the number of type II Na-P_i cotransporters in proximal tubules, as well as in opossum kidney (OK) cells. PTH is known also to lead to an activation of adenylate cyclase and phospholipase C in proximal tubular preparations, as well as in OK cells. In the present study, we investigated the involvement of these two regulatory pathways in OK cells in the PTH-dependent downregulation of the number of type II Na-P_i cotransporters. We have addressed this issue by using pharmacological activators of protein kinase A (PKA) and protein kinase C (PKC), i.e., 8-bromo-cAMP (8-BrcAMP) and -12-O-tetradecanoylphorbol 13-acetate (-TPA), respectively, as well as by the use of synthetic peptide fragments of PTH that activate adenylate cyclase and/or phospholipase C, i.e., PTH-(1-34) and PTH-(3-34), respectively. Our results show that PTH signal transduction via cAMP-dependent, as well as cAMP-independent, pathways leads to a membrane retrieval and degradation of type II Na-P_i cotransporters and, thereby, to the inhibition of Na-P_i cotransport activity. Thereby, the cAMP-independent regulatory pathway leads only to partial effects (~50%).

opossum kidney cells; protein kinase A; protein kinase C; phorbol ester; parathyroid hormone-(3-34)

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