cAMP-dependent and -independent downregulation of type II Na-Pi cotransporters by PTH.
Parathyroid hormone (PTH) leads to the inhibition of Na-Pi cotransport activity and to the downregulation of the number of type II Na-Pi 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-Pi 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 beta-12-O-tetradecanoylphorbol 13-acetate (beta-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-Pi cotransporters and, thereby, to the inhibition of Na-Pi cotransport activity. Thereby, the cAMP-independent regulatory pathway leads only to partial effects (approximately 50%).
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000199:Actins / Q000032:analysis; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002352:Carrier Proteins / Q000502:physiology*; D002999:Clone Cells; D000242:Cyclic AMP / Q000502:physiology*; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D007668:Kidney / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D008855:Microscopy, Electron, Scanning; D009893:Opossums; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D050608:Sodium-Phosphate Cotransporter Proteins; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; D027981:Symporters; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019108:Tight Junctions / Q000648:ultrastructure