| pubmed-article:21303955 | pubmed:abstractText | XL?s, a variant of the stimulatory G protein ?-subunit (Gs?), can mediate receptor-activated cAMP generation and, thus, mimic the actions of Gs? in transfected cells. However, it remains unknown whether XL?s can act in a similar manner in vivo. We have now generated mice with ectopic transgenic expression of rat XL?s in the renal proximal tubule (rptXL?s mice), where Gs? mediates most actions of PTH. Western blots and quantitative RT-PCR showed that, while Gs? and type-1 PTH receptor levels were unaltered, protein kinase A activity and 25-hydroxyvitamin D 1-?-hydroxylase (Cyp27b1) mRNA levels were significantly higher in renal proximal tubules of rptXL?s mice than wild-type littermates. Immunohistochemical analysis of kidney sections showed that the sodium-phosphate cotransporter type 2a was modestly reduced in brush border membranes of male rptXL?s mice compared to gender-matched controls. Serum calcium, phosphorus, and 1,25 dihydroxyvitamin D were within the normal range, but serum PTH was ?30% lower in rptXL?s mice than in controls (152 ± 16 vs. 222 ± 41 pg/ml; P < 0.05). After crossing the rptXL?s mice to mice with ablation of maternal Gnas exon 1 (E1(m-/+)), male offspring carrying both the XL?s transgene and maternal Gnas exon 1 ablation (rptXL?s/E1(m-/+)) were significantly less hypocalcemic than gender-matched E1(m-/+) littermates. Both E1(m-/+) and rptXL?s/E1(m-/+) offspring had higher serum PTH than wild-type littermates, but the degree of secondary hyperparathyroidism tended to be lower in rptXL?s/E1(m-/+) mice. Hence, transgenic XL?s expression in the proximal tubule enhanced Gs?-mediated responses, indicating that XL?s can mimic Gs? in vivo. | lld:pubmed |
