The G protein ? subunit variant XL?s 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) ? subunit (G?s), also encodes a large variant of G?s termed extra-large ? subunit (XL?s), and alterations in XL?s abundance or activity are implicated in various human disorders. Although XL?s, like G?s, stimulates generation of the second messenger cyclic adenosine monophosphate (cAMP), evidence suggests that XL?s and G?s have opposing effects in vivo. We investigated the role of XL?s in mediating signaling by parathyroid hormone (PTH), which activates a G protein-coupled receptor (GPCR) that stimulates both G?s and G?q/11 in renal proximal tubules to maintain phosphate and vitamin D homeostasis. At postnatal day 2 (P2), XL?s 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 G?q/11 signaling, was repressed in renal proximal tubules from XLKO mice. Crossing of XLKO mice with mice overexpressing XL?s specifically in renal proximal tubules rescued the phenotype of the XLKO mice. Overexpression of XL?s 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 XL?s enhances Gq/11 signaling to mediate the renal actions of PTH during early postnatal development.

SUBMITTER: He Q 

PROVIDER: S-EPMC4618482 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature