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Lack of adenylyl cyclase 6 causes pseudohypoparathyroidism (1181.1)
Author(s) -
Fenton Robert,
Murray Fiona,
Dominguez Rieg Jessica,
Tang Tong,
Levi Moshe,
Rieg Timo
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1181.1
Subject(s) - parathyroid hormone , medicine , adenylyl cyclase , endocrinology , biology , adenylate kinase , receptor , immunogold labelling , microbiology and biotechnology , cyclase , biochemistry , calcium , stimulation , ultrastructure , anatomy
Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) enhance phosphate (Pi) excretion by the proximal tubule of the kidney via retrieval of the Na+‐dependent Pi transporters (Npt2a & Npt2c). PTH activates adenylyl cyclase (AC) via PTH 1 receptors and stimulates cAMP/PKA signaling. However, the precise role and isoform(s) of AC in Pi homeostasis are unknown. We previously showed that mice lacking AC6 (AC6‐/‐) have increased plasma PTH and FGF23 while having comparable plasma Pi concentrations. Acute activation of the Ca2+ sensing receptor or feeding a zero Pi diet almost completely suppressed plasma PTH in AC6‐/‐ and wild‐type (WT) mice, indicating secondary hyperparathyroidism. We now studied the abundance and localization of Npt2a and Npt2c. Immunofluorescence and quantitative confocal laser scanning microscopy showed a reduced renal Npt2a and Npt2c protein abundance in AC6‐/‐ mice. Immunogold labeling indicated a tendency for a reduced total number of gold particles per proximal tubule cell in AC6‐/‐ mice (510±53 vs 715±119, P=0.09). In contrast to the Npt2a distribution under basal conditions in WT mice (53, 28 and 17% reside in microvilli, lysosomes and intracellular, respectively), in AC6‐/‐ mice the majority of Npt2a resides in lysosomes (12, 77 and 10%, respectively). The distribution of Npt2a gold particles 1h after PTH treatment (200 µg/kg) in WT mice was shifted, with less particles residing in the apical microvilli (24%) compared to lysosomes (40%) and intracellular compartments (40%) whereas the distribution in AC6‐/‐ was unchanged. We conclude that AC6 in the proximal tubule determines Npt2a trafficking and urinary phosphate excretion, such that AC6‐/‐ mice have pseudohypoparathyroidism. Grant Funding Source : P01 HL66941, HL088426, 1101BX001515, R01DK066029, P30DK079337 and 10SDG2610034