G?s is critical for the actions of PTH and PTHrP. The gene encoding G?s (GNAS) also gives rise to XL?s, which is expressed in various tissues including osteoblastic and renal cells. XL?s can mimic G?s by stimulating cAMP generation in response PTH, although it is also predicted to have unique actions. Mutations in GNAS are found in several human diseases that impair signaling through the PTH/PTHrP receptor (PTHR). Most of these mutations affect both G?s and XL?s. Studies in mice and humans indicate that XL?s plays important roles in physiology and human disease, but the actions of XL?s remain poorly understood. Our recent studies have provided novel insights into the cellular actions of XL?s, and together with our findings obtained from XL?s knockout (XLKO) mice, these led us to hypothesize that XL?s is necessary for the regulation of calcium and phosphorus metabolism in vivo.
In Aim 1 of the current proposal, we will address whether XL?s is necessary for PTH-mediated actions in the renal proximal tubule during early postnatal development. We will determine a) whether proximal tubular actions of PTH in XLKO mice are impaired and b) whether the PTH resistance phenotype in XLKO mice is rescued by transgenically reconstituting XL?s expression in the proximal tubule.
In Aim 2, we will address whether XL?s allows PTH actions to be sustained in the renal proximal tubule, which could explain the PTH resistance phenotype in XLKO mice. We will thus determine a) whether PTHR internalization is enhanced in the proximal tubule of XLKO mice;b) whether the PTH resistance phenotype in XLKO mice can be rescued by a mutant PTHR with sustained activity or by overexpressing G?s in the proximal tubule;and c) whether the interaction of XL?s with dynamin influences PTH actions. These studies will provide novel insights into the actions of PTH and XL?s in the renal proximal tubule, and these will be applicable to the actions of these proteins in skeletal tissues. Our results will also help reveal the roles of XL?s in other systems, in addition to improving our knowledge of the mechanisms underlying the diseases caused by GNAS mutations. Given that XL?s can activate the ubiquitous cAMP signaling pathway, our results will likely have even broader implications for human health and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK073911-07
Application #
8675845
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Malozowski, Saul N
Project Start
2005-12-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Bastepe, Murat (2017) GNAS mutations and heterotopic ossification. Bone :
He, Qing; Bouley, Richard; Liu, Zun et al. (2017) Large G protein ?-subunit XL?s limits clathrin-mediated endocytosis and regulates tissue iron levels in vivo. Proc Natl Acad Sci U S A 114:E9559-E9568
Reyes, Monica; Karaca, Anara; Bastepe, Murat et al. (2017) A novel deletion involving GNAS exon 1 causes PHP1A and further refines the region required for normal methylation at exon A/B. Bone 103:281-286
Bastepe, Murat; Turan, Serap; He, Qing (2017) Heterotrimeric G proteins in the control of parathyroid hormone actions. J Mol Endocrinol 58:R203-R224
Zhu, Yan; He, Qing; Aydin, Cumhur et al. (2016) Ablation of the Stimulatory G Protein ?-Subunit in Renal Proximal Tubules Leads to Parathyroid Hormone-Resistance With Increased Renal Cyp24a1 mRNA Abundance and Reduced Serum 1,25-Dihydroxyvitamin D. Endocrinology 157:497-507
Wentworth, Kelly; Hsing, Alyssa; Urrutia, Ashley et al. (2016) A Novel T55A Variant of Gs ? Associated with Impaired cAMP Production, Bone Fragility, and Osteolysis. Case Rep Endocrinol 2016:2691385
Turan, Serap; Thiele, Susanne; Tafaj, Olta et al. (2015) Evidence of hormone resistance in a pseudo-pseudohypoparathyroidism patient with a novel paternal mutation in GNAS. Bone 71:53-7
Turan, Serap; Bastepe, Murat (2015) GNAS Spectrum of Disorders. Curr Osteoporos Rep 13:146-58
He, Qing; Zhu, Yan; Corbin, Braden A et al. (2015) The G protein ? subunit variant XL?s promotes inositol 1,4,5-trisphosphate signaling and mediates the renal actions of parathyroid hormone in vivo. Sci Signal 8:ra84
Turan, Serap; Fernandez-Rebollo, Eduardo; Aydin, Cumhur et al. (2014) Postnatal establishment of allelic G?s silencing as a plausible explanation for delayed onset of parathyroid hormone resistance owing to heterozygous G?s disruption. J Bone Miner Res 29:749-60

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