title: Down-regulation of protein kinase C by parathyroid hormone and mezerein differentially modulates cAMP production and phosphate transport in opossum kidney cells.
abstract: We examined the effects of prolonged exposure to parathyroid hormone (PTH) and the protein kinase C (PKC) activator mezerein (MEZ) on cyclic adenosine monophosphate (cAMP) production, PKC activity, and Na(+)-dependent phosphate (Na/Pi) transport in an opossum kidney cell line (OK/E). A 5 minute exposure to PTH stimulated, while a 6 h incubation reduced, cAMP production, Na/Pi transport was maximally inhibited under desensitizing conditions and was not affected by reintroduction of the hormone. MEZ pretreatment (6 h) enhanced PTH-, cholera toxin (CTX)-, and forskolin (FSK)-stimulated cAMP production, suggesting enhanced Gs alpha coupling and increased adenylyl cyclase activity. However, PKA- and PKC-dependent regulation of Na/Pi were blocked in MEZ-treated cells. The PTH-induced decrease in cAMP production was associated with a reduction in membrane-associated PKC activity while MEZ-induced increases in cAMP production were accompanied by decreases in membrane and cytosolic PKC activity. Enhanced cAMP production was not accompanied by significant changes in PTH/PTH related peptide (PTHrP) receptor affinity or number, nor was the loss of Na/Pi transport regulation associated with changes in PKA activity. The results indicate that down-regulation of PKC by PTH or MEZ differentially modulates cAMP production and regulation of Na/Pi transport. The distinct effects of PTH and MEZ on PKC activity suggest that agonist-specific activation and/or down-regulation of PKC isozyme(s) may be involved in the observed changes in cAMP production and Na/Pi transport.
authors.affiliation: Department of Pharmacology, University of Missouri School of Medicine, Columbia, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Cole
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001665:Binding Sites; D001693:Biological Transport, Active; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000633:toxicity; D005576:Colforsin / Q000633:toxicity; D000242:Cyclic AMP / Q000096:biosynthesis*; D004224:Diterpenes; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009893:Opossums; D010281:Parathyroid Hormone / Q000633:toxicity*; D010710:Phosphates / Q000378:metabolism*; D010759:Phosphorus Isotopes; D011493:Protein Kinase C / Q000378:metabolism*; D012964:Sodium / Q000494:pharmacology; D013729:Terpenes / Q000633:toxicity*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004224:Diterpenes; D010281:Parathyroid Hormone; D010710:Phosphates; D010759:Phosphorus Isotopes; D013729:Terpenes; D005576:Colforsin; C011309:mezerein; D002772:Cholera Toxin; D012964:Sodium; D000242:Cyclic AMP; D011493:Protein Kinase C