title: The G protein α subunit variant XLαs promotes inositol 1,4,5-trisphosphate signaling and mediates the renal actions of parathyroid hormone in vivo.
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.
authors: Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors: Qing
authors: Q
authors: He
authors: Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors: Yan
authors: Y
authors: Zhu
authors: Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors: Braden A
authors: BA
authors: Corbin
authors: Department of Cellular and Molecular Physiology, Institute of Translational Medicine University of Liverpool, Liverpool L69 3BX, UK.
authors: Antonius
authors: A
authors: Plagge
authors: Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. bastepe@helix.mgh.harvard.edu.
authors: Murat
authors: M
authors: Bastepe
mesh_terms: D000818:Animals; D002864:Chromogranins; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000235:genetics / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010281:Parathyroid Hormone / Q000378:metabolism / Q000494:pharmacology*; D015290:Second Messenger Systems / Q000187:drug effects* / Q000502:physiology; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000235:genetics / Q000378:metabolism
chemical_list: D002864:Chromogranins; D010281:Parathyroid Hormone; C493555:Slc34a1 protein, mouse; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; C498642:Gnas protein, mouse; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019205:GTP-Binding Protein alpha Subunits, Gs