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.

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