NDLI: Acute Down-regulation of Sodium-dependent Phosphate Transporter NPT2a Involves Predominantly the cAMP/PKA Pathway as Revealed by Signaling-selective Parathyroid Hormone Analogs

Content Provider	PubMed Central
Author	Nagai, So Okazaki, Makoto Segawa, Hiroko Clemens, Bergwitz Dean, Thomas Potts, John T. Mahon, Matthew J. Gardella, Thomas J. Jüppner, Harald
Abstract	The parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor (PTHR1) in cells of the renal proximal tubule mediates the reduction in membrane expression of the sodium-dependent Pi co-transporters, NPT2a and NPT2c, and thus suppresses the re-uptake of Pi from the filtrate. In most cell types, the liganded PTHR1 activates GαS/adenylyl cyclase/cAMP/PKA (cAMP/PKA) and Gαq/11/phospholipase C/phosphatidylinositol 1,4,5-trisphosphate (IP3)/Ca2+/PKC (IP3/PKC) signaling pathways, but the relative roles of each pathway in mediating renal regulation Pi transport remain uncertain. We therefore explored the signaling mechanisms involved in PTH-dependent regulation of NPT2a function using potent, long-acting PTH analogs, M-PTH(1–28) (where M = Ala1,12, Aib3, Gln10, Har11, Trp14, and Arg19) and its position 1-modified variant, Trp1-M-PTH(1–28), designed to be phospholipase C-deficient. In cell-based assays, both M-PTH(1–28) and Trp1-M-PTH(1–28) exhibited potent and prolonged cAMP responses, whereas only M-PTH(1–28) was effective in inducing IP3 and intracellular calcium responses. In opossum kidney cells, a clonal cell line in which the PTHR1 and NPT2a are endogenously expressed, M-PTH(1–28) and Trp1-M-PTH(1–28) each induced reductions in 32P uptake, and these responses persisted for more than 24 h after ligand wash-out, whereas that of PTH(1–34) was terminated by 4 h. When injected into wild-type mice, both M-modified PTH analogs induced prolonged reductions in blood Pi levels and commensurate reductions in NPT2a expression in the renal brush border membrane. Our findings suggest that the acute down-regulation of NPT2a expression by PTH ligands involves mainly the cAMP/PKA signaling pathway and are thus consistent with the elevated blood Pi levels seen in pseudohypoparathyroid patients, in whom Gαs-mediated signaling in renal proximal tubule cells is defective.
Related Links	http://dx.doi.org/10.1074/jbc.m110.198416
Ending Page	1626
Page Count	9
Starting Page	1618
File Format	PDF
ISSN	00219258
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	2
Volume Number	286
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2011-01-14
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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Acute Down-regulation of Sodium-dependent Phosphate Transporter NPT2a Involves Predominantly the cAMP/PKA Pathway as Revealed by Signaling-selective Parathyroid Hormone Analogs

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