XLas Relative to Gsa in Bone and Mineral Ion Metabolism

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DESCRIPTION (provided by applicant): Gαs is critical for the actions of PTH and PTHrP. The gene encoding Gαs (GNAS) also gives rise to XLαs, which is expressed in various tissues including osteoblastic and renal cells. XLαs can mimic Gαs 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 Gαs and XLαs. Studies in mice and humans indicate that XLαs plays important roles in physiology and human disease, but the actions of XLαs remain poorly understood. Our recent studies have provided novel insights into the cellular actions of XLαs, and together with our findings obtained from XLαs knockout (XLKO) mice, these led us to hypothesize that XLαs is necessary for the regulation of calcium and phosphorus metabolism in vivo. In Aim 1 of the current proposal, we will address whether XLαs 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 XLαs expression in the proximal tubule. In Aim 2, we will address whether XLαs 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 Gαs in the proximal tubule; and c) whether the interaction of XLαs with dynamin influences PTH actions. These studies will provide novel insights into the actions of PTH and XLαs 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 XLαs in other systems, in addition to improving our knowledge of the mechanisms underlying the diseases caused by GNAS mutations. Given that XLαs can activate the ubiquitous cAMP signaling pathway, our results will likely have even broader implications for human health and disease.