The G protein α subunit variant XLαs promotes inositol 1,4,5-trisphosphate signaling and mediates the renal actions of parathyroid hormone in vivo



He, Qing, Zhu, Yan, Corbin, Braden A, Plagge, Antonius ORCID: 0000-0001-6592-1343 and Bastepe, Murat
(2015) The G protein α subunit variant XLαs promotes inositol 1,4,5-trisphosphate signaling and mediates the renal actions of parathyroid hormone in vivo. Science Signaling, 8 (391). ra84-.

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Abstract

GNAS, which encodes the stimulatory G protein (heterotrimeric guanine nucleotide–binding protein) α subunit (Gαs), also encodes a large variant of Gαs termed extra-large α subunit (XLαs), and alterations in XLαs abundance or activity are implicated in various human disorders. Although XLαs, like Gαs, stimulates generation of the second messenger cyclic adenosine monophosphate (cAMP), evidence suggests that XLαs and Gαs have opposing effects in vivo. We investigated the role of XLαs in mediating signaling by parathyroid hormone (PTH), which activates a G protein–coupled receptor (GPCR) that stimulates both Gαs and Gαq/11 in renal proximal tubules to maintain phosphate and vitamin D homeostasis. At postnatal day 2 (P2), XLαs knockout (XLKO) mice exhibited hyperphosphatemia, hypocalcemia, and increased serum concentrations of PTH and 1,25-dihydroxyvitamin D. The ability of PTH to reduce serum phosphate concentrations was impaired, and the abundance of the sodium phosphate cotransporter Npt2a in renal brush border membranes was reduced in XLKO mice, whereas PTH-induced cAMP excretion in the urine was modestly increased. Basal and PTH-stimulated production of inositol 1,4,5-trisphosphate (IP3), which is the second messenger produced by Gαq/11 signaling, was repressed in renal proximal tubules from XLKO mice. Crossing of XLKO mice with mice overexpressing XLαs specifically in renal proximal tubules rescued the phenotype of the XLKO mice. Overexpression of XLαs in HEK 293 cells enhanced IP3 generation in unstimulated cells and in cells stimulated with PTH or thrombin, which acts through a Gq/11-coupled receptor. Together, our findings suggest that XLαs enhances Gq/11 signaling to mediate the renal actions of PTH during early postnatal development.

Item Type: Article
Uncontrolled Keywords: Kidney Tubules, Proximal, Animals, Mice, Knockout, Humans, Mice, Inositol 1,4,5-Trisphosphate, Parathyroid Hormone, GTP-Binding Protein alpha Subunits, Gq-G11, GTP-Binding Protein alpha Subunits, Gs, Chromogranins, Cyclic AMP, Second Messenger Systems, Sodium-Phosphate Cotransporter Proteins, Type IIa, HEK293 Cells
Depositing User: Symplectic Admin
Date Deposited: 21 Sep 2016 08:50
Last Modified: 19 Jan 2023 07:37
DOI: 10.1126/scisignal.aaa9953
Open Access URL: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC461848...
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3001034