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.
XL?s is a variant of G?s, which is important for the actions of parathyroid hormone. Mutations in the gene making these two proteins cause different human diseases that affect the bone and mineral metabolism. Unlike G?s, functional roles of XL?s are unknown. We aim to determine the role XL?s in mediating the actions of parathyroid hormone to learn more about the mechanisms underlying those diseases.
|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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|Turan, Serap; Bastepe, Murat (2013) The GNAS complex locus and human diseases associated with loss-of-function mutations or epimutations within this imprinted gene. Horm Res Paediatr 80:229-41|
|Fernández-Rebollo, Eduardo; Maeda, Akira; Reyes, Monica et al. (2012) Loss of XL?s (extra-large ?s) imprinting results in early postnatal hypoglycemia and lethality in a mouse model of pseudohypoparathyroidism Ib. Proc Natl Acad Sci U S A 109:6638-43|
|Mahon, M J (2012) The parathyroid hormone receptorsome and the potential for therapeutic intervention. Curr Drug Targets 13:116-28|
|Liu, Zun; Segawa, Hiroko; Aydin, Cumhur et al. (2011) Transgenic overexpression of the extra-large Gs? variant XL?s enhances Gs?-mediated responses in the mouse renal proximal tubule in vivo. Endocrinology 152:1222-33|
|Puzhko, Svetlana; Goodyer, Cynthia Gates; Kerachian, Mohammad Amin et al. (2011) Parathyroid hormone signaling via Gýýs is selectively inhibited by an NH(2)-terminally truncated Gýýs: implications for pseudohypoparathyroidism. J Bone Miner Res 26:2473-85|
|Fernandez-Rebollo, Eduardo; Perez de Nanclares, Guiomar; Lecumberri, Beatriz et al. (2011) Exclusion of the GNAS locus in PHP-Ib patients with broad GNAS methylation changes: evidence for an autosomal recessive form of PHP-Ib? J Bone Miner Res 26:1854-63|
|Wu, Joy Y; Aarnisalo, Piia; Bastepe, Murat et al. (2011) Gs? enhances commitment of mesenchymal progenitors to the osteoblast lineage but restrains osteoblast differentiation in mice. J Clin Invest 121:3492-504|
|Mahon, Matthew J (2011) Apical membrane segregation of phosphatidylinositol-4,5-bisphosphate influences parathyroid hormone 1 receptor compartmental signaling and localization via direct regulation of ezrin in LLC-PK1 cells. Cell Signal 23:1659-68|
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