{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T11:33:22Z","timestamp":1778672002404,"version":"3.51.4"},"reference-count":62,"publisher":"The Endocrine Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>PTH regulates serum calcium, phosphate, and 1,25-dihydroxyvitamin D (1,25(OH)2D) levels by acting on bone and kidney. In renal proximal tubules (PTs), PTH inhibits reabsorption of phosphate and stimulates the synthesis of 1,25(OH)2D. The PTH receptor couples to multiple G proteins. We here ablated the \u03b1-subunit of the stimulatory G protein (Gs\u03b1) in mouse PTs by using Cre recombinase driven by the promoter of type-2 sodium-glucose cotransporter (Gs\u03b1Sglt2KO mice). Gs\u03b1Sglt2KO mice were normophosphatemic but displayed, relative to controls, hypocalcemia (1.19 \u00b10.01 vs 1.23 \u00b10.01 mmol\/L; P &amp;lt; .05), reduced serum 1,25(OH)2D (59.3 \u00b17.0 vs 102.5 \u00b112.2 pmol\/L; P &amp;lt; .05), and elevated serum PTH (834 \u00b1133 vs 438 \u00b159 pg\/mL; P &amp;lt; .05). PTH-induced elevation in urinary cAMP excretion was blunted in Gs\u03b1Sglt2KO mice (2- vs 4-fold over baseline in controls; P &amp;lt; .05). Relative to baseline in controls, PTH-induced reduction in serum phosphate tended to be blunted in Gs\u03b1Sglt2KO mice (\u22120.39 \u00b10.33 vs \u22121.34 \u00b10.36 mg\/dL; P = .07). Gs\u03b1Sglt2KO mice showed elevated renal vitamin D 24-hydroxylase and bone fibroblast growth factor-23 (FGF23) mRNA abundance (\u223c3.4- and \u223c11-fold over controls, respectively; P &amp;lt; .05) and tended to have elevated serum FGF23 (829 \u00b176 vs 632 \u00b160 pg\/mL in controls; P = .07). Heterozygous mice having constitutive ablation of the maternal Gs\u03b1 allele (E1m\u2212\/+) (model of pseudohypoparathyroidism type-Ia), in which Gs\u03b1 levels in PT are reduced, also exhibited elevated serum FGF23 (474 \u00b120 vs 374 \u00b127 pg\/mL in controls; P &amp;lt; .05). Our findings indicate that Gs\u03b1 is required in PTs for suppressing renal vitamin D 24-hydroxylase mRNA levels and for maintaining normal serum 1,25(OH)2D.<\/jats:p>","DOI":"10.1210\/en.2015-1639","type":"journal-article","created":{"date-parts":[[2015,12,15]],"date-time":"2015-12-15T19:34:24Z","timestamp":1450208064000},"page":"497-507","source":"Crossref","is-referenced-by-count":10,"title":["Ablation of the Stimulatory G Protein \u03b1-Subunit in Renal Proximal Tubules Leads to Parathyroid Hormone-Resistance With Increased Renal Cyp24a1 mRNA Abundance and Reduced Serum 1,25-Dihydroxyvitamin D"],"prefix":"10.1210","volume":"157","author":[{"given":"Yan","family":"Zhu","sequence":"first","affiliation":[{"name":"Endocrine Unit (Z.Y., Q.H., C.A., H.J., M.B.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"He","sequence":"first","affiliation":[{"name":"Endocrine Unit (Z.Y., Q.H., C.A., H.J., M.B.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cumhur","family":"Aydin","sequence":"first","affiliation":[{"name":"Endocrine Unit (Z.Y., Q.H., C.A., H.J., M.B.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114"},{"name":"Department of Endodontics (C.A.), G\u00fclhane Military Medical Academy, 06018 Ankara, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabelle","family":"Rubera","sequence":"first","affiliation":[{"name":"Faculty of Medicine (I.R., M.T.), Universit\u00e9 de Nice Sophia Antipolis, 06107 Nice, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michel","family":"Tauc","sequence":"first","affiliation":[{"name":"Faculty of Medicine (I.R., M.T.), Universit\u00e9 de Nice Sophia Antipolis, 06107 Nice, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Chen","sequence":"first","affiliation":[{"name":"Metabolic Diseases Branch (M.C., L.S.W.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lee S.","family":"Weinstein","sequence":"first","affiliation":[{"name":"Metabolic Diseases Branch (M.C., L.S.W.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vladimir","family":"Marshansky","sequence":"first","affiliation":[{"name":"Program in Membrane Biology (V.M.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harald","family":"J\u00fcppner","sequence":"first","affiliation":[{"name":"Endocrine Unit (Z.Y., Q.H., C.A., H.J., M.B.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114"},{"name":"Pediatric Nephrology Unit (H.J.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Murat","family":"Bastepe","sequence":"first","affiliation":[{"name":"Endocrine Unit (Z.Y., Q.H., C.A., H.J., M.B.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","published-online":{"date-parts":[[2015,12,15]]},"reference":[{"key":"2020071612015814100_B1","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1146\/annurev.med.051308.111339","article-title":"Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23","volume":"61","author":"Bergwitz","year":"2010","journal-title":"Annu Rev Med"},{"key":"2020071612015814100_B2","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/nrendo.2011.218","article-title":"Skeletal secretion of FGF-23 regulates phosphate and vitamin D metabolism","volume":"8","author":"Quarles","year":"2012","journal-title":"Nat Rev Endocrinol"},{"key":"2020071612015814100_B3","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1038\/ki.2014.316","article-title":"Molecular interactions of FGF23 and PTH in phosphate regulation","volume":"86","author":"Lanske","year":"2014","journal-title":"Kidney Int"},{"key":"2020071612015814100_B4","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/nrneph.2010.17","article-title":"Recent advances in renal phosphate handling","volume":"6","author":"Farrow","year":"2010","journal-title":"Na Rev Nephrol"},{"key":"2020071612015814100_B5","doi-asserted-by":"crossref","DOI":"10.1002\/9781118453926.ch29","article-title":"Vitamin D: production, metabolism, mechanism of action, and clinical requirements","volume-title":"Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism","author":"Bikle","year":"2013","edition":"8th ed"},{"key":"2020071612015814100_B6","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.1210\/endo.132.5.8386606","article-title":"Cloned, stably expressed parathyroid hormone (PTH)\/PTH-related peptide receptors activate multiple messenger signals and biological responses in LLC-PK1 kidney cells","volume":"132","author":"Bringhurst","year":"1993","journal-title":"Endocrinology"},{"key":"2020071612015814100_B7","first-page":"F720","article-title":"cAMP-dependent and -independent downregulation of type II Na-Pi cotransporters by PTH","volume":"276","author":"Pfister","year":"1999","journal-title":"Am J 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revealed by signaling-selective parathyroid hormone analogs","volume":"286","author":"Nagai","year":"2011","journal-title":"J Biol Chem"},{"key":"2020071612015814100_B11","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1210\/en.2012-2240","article-title":"Activation of a non-cAMP\/PKA signaling pathway downstream of the PTH\/PTHrP receptor is essential for a sustained hypophosphatemic response to PTH infusion in male mice","volume":"154","author":"Guo","year":"2013","journal-title":"Endocrinology"},{"key":"2020071612015814100_B12","doi-asserted-by":"crossref","first-page":"2502","DOI":"10.1172\/JCI107065","article-title":"Hormonal control of the renal conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol","volume":"51","author":"Rasmussen","year":"1972","journal-title":"J Clin Invest"},{"key":"2020071612015814100_B13","first-page":"569","article-title":"Effects of nucleotides, hormones, ions, and 1,25-dihydroxycholecalciferon on 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Albright hereditary osteodystrophy: no evidence of genomic imprinting","volume":"31","author":"Schuster","year":"1994","journal-title":"J Med Genet"},{"key":"2020071612015814100_B25","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1002\/ajmg.10751","article-title":"Constitutional deletion of chromosome 20q in two patients affected with albright hereditary osteodystrophy","volume":"113","author":"Aldred","year":"2002","journal-title":"Am J Med Genet"},{"key":"2020071612015814100_B26","doi-asserted-by":"crossref","first-page":"3028","DOI":"10.1210\/jc.2009-1451","article-title":"Progressive osseous heteroplasia: a model for the imprinting effects of GNAS inactivating mutations in humans","volume":"95","author":"Lebrun","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612015814100_B27","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1111\/j.1440-0960.2010.00722.x","article-title":"Three cases of osteoma cutis occurring in infancy. A brief overview of osteoma cutis and its association with pseudo-pseudohypoparathyroidism","volume":"52","author":"Ward","year":"2011","journal-title":"Australas J Dermatol"},{"key":"2020071612015814100_B28","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1111\/j.1365-2230.2011.04292.x","article-title":"Linear skin atrophy preceding calcinosis cutis in pseudo-pseudohypoparathyroidism","volume":"37","author":"Lau","year":"2012","journal-title":"Clin Exp Dermatol"},{"key":"2020071612015814100_B29","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.bone.2014.10.006","article-title":"Evidence of hormone resistance in a pseudo-pseudohypoparathyroidism patient with a novel paternal mutation in GNAS","volume":"71","author":"Turan","year":"2015","journal-title":"Bone"},{"key":"2020071612015814100_B30","doi-asserted-by":"crossref","first-page":"4697","DOI":"10.1210\/en.2005-0681","article-title":"A mouse model of Albright hereditary osteodystrophy generated by targeted disruption of exon 1 of the Gnas gene","volume":"146","author":"Germain-Lee","year":"2005","journal-title":"Endocrinology"},{"key":"2020071612015814100_B31","doi-asserted-by":"crossref","first-page":"7386","DOI":"10.1073\/pnas.0408268102","article-title":"Alternative Gnas gene products have opposite effects on glucose and lipid metabolism","volume":"102","author":"Chen","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612015814100_B32","doi-asserted-by":"crossref","first-page":"2050","DOI":"10.1097\/01.ASN.0000133023.89251.01","article-title":"Specific Cre\/Lox recombination in the mouse proximal tubule","volume":"15","author":"Rubera","year":"2004","journal-title":"J Am Soc Nephrol"},{"key":"2020071612015814100_B33","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1210\/en.2010-1034","article-title":"Transgenic overexpression of the extra-large Gs\u03b1 variant XL\u03b1s enhances Gs\u03b1-mediated responses in the mouse renal proximal tubule in vivo","volume":"152","author":"Liu","year":"2011","journal-title":"Endocrinology"},{"key":"2020071612015814100_B34","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1159\/000355384","article-title":"The GNAS complex locus and human diseases associated with loss-of-function mutations or epimutations within this imprinted gene","volume":"80","author":"Turan","year":"2013","journal-title":"Horm Res Paediatr"},{"key":"2020071612015814100_B35","first-page":"F129","article-title":"Distribution of epithelial ankyrin (Ank3) spliceoforms in renal proximal and distal tubules","volume":"274","author":"Doctor","year":"1998","journal-title":"Am J Physiol"},{"key":"2020071612015814100_B36","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat Methods"},{"key":"2020071612015814100_B37","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1242\/dev.049437","article-title":"Polycystin-dependent fluid flow sensing targets histone deacetylase 5 to prevent the development of renal cysts","volume":"137","author":"Xia","year":"2010","journal-title":"Development"},{"key":"2020071612015814100_B38","doi-asserted-by":"crossref","first-page":"4003","DOI":"10.1172\/JCI58662","article-title":"PGC-1\u03b1 promotes recovery after acute kidney injury during systemic inflammation in mice","volume":"121","author":"Tran","year":"2011","journal-title":"J Clin Invest"},{"key":"2020071612015814100_B39","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1007\/s00109-013-1015-3","article-title":"Proximal tubule specific knockout of the Na(+)\/H(+) exchanger NHE3: effects on bicarbonate absorption and ammonium excretion","volume":"91","author":"Li","year":"2013","journal-title":"J Mol Med"},{"key":"2020071612015814100_B40","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1002\/dvg.20335","article-title":"A global double-fluorescent Cre reporter mouse","volume":"45","author":"Muzumdar","year":"2007","journal-title":"Genesis"},{"key":"2020071612015814100_B41","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nn.2467","article-title":"A robust and high-throughput Cre reporting and characterization system for the whole mouse brain","volume":"13","author":"Madisen","year":"2010","journal-title":"Nat Neurosci"},{"key":"2020071612015814100_B42","doi-asserted-by":"crossref","first-page":"F199","DOI":"10.1152\/ajprenal.00513.2010","article-title":"Is caveolin involved in normal proximal tubule function? Presence in model PT systems but absence in situ","volume":"300","author":"Zhuang","year":"2011","journal-title":"Am J Physiol Renal Physiol"},{"key":"2020071612015814100_B43","doi-asserted-by":"crossref","first-page":"1832","DOI":"10.1172\/JCI106149","article-title":"Pseudohypoparathyroidism: defective excretion of 3\u2032,5\u2032-AMP in response to parathyroid hormone","volume":"48","author":"Chase","year":"1969","journal-title":"J Clin Invest"},{"key":"2020071612015814100_B44","doi-asserted-by":"crossref","first-page":"5864","DOI":"10.1073\/pnas.1301674110","article-title":"Critical role of parathyroid hormone (PTH) receptor-1 phosphorylation in regulating acute responses to PTH","volume":"110","author":"Maeda","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612015814100_B45","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1073\/pnas.95.4.1387","article-title":"Parathyroid hormone activation of the 25-hydroxyvitamin D3-1a-hydroxylase gene promoter","volume":"95","author":"Brenza","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612015814100_B46","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1172\/JCI116972","article-title":"The human kidney low affinity Na+\/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose","volume":"93","author":"Kanai","year":"1994","journal-title":"J Clin Invest"},{"key":"2020071612015814100_B47","doi-asserted-by":"crossref","first-page":"29365","DOI":"10.1074\/jbc.270.49.29365","article-title":"Molecular characteristics of Na(+)-coupled glucose transporters in adult and embryonic rat kidney","volume":"270","author":"You","year":"1995","journal-title":"J Biol Chem"},{"key":"2020071612015814100_B48","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1007\/s00424-014-1619-7","article-title":"Localizations of Na-D-glucose cotransporters SGLT1 and SGLT2 in human kidney and of SGLT1 in human small intestine, liver, lung, and heart","volume":"467","author":"Vrhovac","year":"2015","journal-title":"Pflugers Arch"},{"key":"2020071612015814100_B49","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1073\/pnas.78.2.1199","article-title":"Localization of 25-hydroxyvitamin D3 1 \u03b1-hydroxylase and 24-hydroxylase along the rat nephron","volume":"78","author":"Kawashima","year":"1981","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612015814100_B50","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1007\/s00424-010-0841-1","article-title":"Acute parathyroid hormone differentially regulates renal brush border membrane phosphate cotransporters","volume":"460","author":"Picard","year":"2010","journal-title":"Pflugers Arch"},{"key":"2020071612015814100_B51","doi-asserted-by":"crossref","first-page":"F1076","DOI":"10.1152\/ajprenal.00632.2012","article-title":"Parathyroid hormone (PTH) decreases sodium-phosphate cotransporter type IIa (NpT2a) mRNA stability","volume":"304","author":"Murray","year":"2013","journal-title":"Am J Physiol Renal Physiol"},{"key":"2020071612015814100_B52","first-page":"E793","article-title":"Expression of 25(OH)D3 24-hydroxylase in distal nephron: coordinate regulation by 1,25(OH)2D3 and cAMP or 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