| First Author | He Q | Year | 2015 |
| Journal | Sci Signal | Volume | 8 |
| Issue | 391 | Pages | ra84 |
| PubMed ID | 26307011 | Mgi Jnum | J:258607 |
| Mgi Id | MGI:6142147 | Doi | 10.1126/scisignal.aaa9953 |
| Citation | He Q, et al. (2015) The G protein alpha subunit variant XLalphas promotes inositol 1,4,5-trisphosphate signaling and mediates the renal actions of parathyroid hormone in vivo. Sci Signal 8(391):ra84 |
| abstractText | GNAS, which encodes the stimulatory G protein (heterotrimeric guanine nucleotide-binding protein) alpha subunit (Galphas), also encodes a large variant of Galphas termed extra-large alpha subunit (XLalphas), and alterations in XLalphas abundance or activity are implicated in various human disorders. Although XLalphas, like Galphas, stimulates generation of the second messenger cyclic adenosine monophosphate (cAMP), evidence suggests that XLalphas and Galphas have opposing effects in vivo. We investigated the role of XLalphas in mediating signaling by parathyroid hormone (PTH), which activates a G protein-coupled receptor (GPCR) that stimulates both Galphas and Galphaq/11 in renal proximal tubules to maintain phosphate and vitamin D homeostasis. At postnatal day 2 (P2), XLalphas 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 Galphaq/11 signaling, was repressed in renal proximal tubules from XLKO mice. Crossing of XLKO mice with mice overexpressing XLalphas specifically in renal proximal tubules rescued the phenotype of the XLKO mice. Overexpression of XLalphas 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 XLalphas enhances Gq/11 signaling to mediate the renal actions of PTH during early postnatal development. |
