Research ArticleG Protein Signaling

The G protein α subunit variant XLαs promotes inositol 1,4,5-trisphosphate signaling and mediates the renal actions of parathyroid hormone in vivo

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Science Signaling  25 Aug 2015:
Vol. 8, Issue 391, pp. ra84
DOI: 10.1126/scisignal.aaa9953

An extra-large signaling role

G protein–coupled receptors (GPCRs) stimulate heterotrimeric G proteins. G proteins of the Gs family stimulate generation of the second messenger cAMP, whereas Gq/11 proteins stimulate generation of the second messenger IP3. The gene encoding the Gs α subunit (Gαs) also encodes a structurally similar, extra-large variant, XLαs, which also stimulates cAMP generation. He et al. found that the effects of parathyroid hormone (PTH), which stimulates both cAMP and IP3 production by activating a GPCR that couples to both Gs and Gq/11, on the kidney were impaired in XLαs-deficient mice. However, rather than producing substantially less cAMP, kidney cells from the XLαs-deficient mice had a defect in generating IP3, which was restored when the mice were crossed with transgenic mice overexpressing XLαs in renal proximal tubules. Together, these data suggest that XLαs plays a physiological role in stimulating IP3 signaling.


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

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