Variable imprinting of the heterotrimeric G protein G(s) alpha-subunit within different segments of the nephron

The heterotrimeric G protein G(s) is required for hormone-stimulated intrac ellular cAMP generation because it couples hormone receptors to the enzyme adenylyl cyclase. Hormones that activate G(s) in the kidney include parathy roid hormone, glucagon, calcitonin, and vasopressin. Recently, it has been demonstrated that the G(s)alpha gene is imprinted in a tissue-specific mann er, leading to preferential expression of G(s)alpha from the maternal allel e in some tissues. In the kidney, G(s)alpha is imprinted in the proximal tu bule but not in more distal nephron segments, such as the thick ascending l imb or collecting duct. This most likely explains why in both humans and mi ce heterozygous mutations in the maternal allele lead to parathyroid hormon e resistance in the proximal tubule whereas mutations in the paternal allel e do not. In contrast, heterozygous mutations have little effect on vasopre ssin action in the collecting ducts. In mice with heterozygous null G(s)alp ha mutations (both those with mutations on the maternal or paternal allele) , expression of the Na-K-2Cl cotransporter was decreased in the thick ascen ding limb, suggesting that its expression is regulated by cAMP. The G,cli g enes also generate alternative, oppositely imprinted transcripts encoding X L alpha s, a G(s)alpha isoform with a long NH2-terminal extension, and NESP 55, a chromogranin-like neurosecretory protein. The role, if any, of these proteins in renal physiology is unknown.