Generation of a floxed Gnsa gene for the G-protein Gs alpha (G_salpha) for the construction of conditional knockout mice. The heterotrimeric G protein G_salpha couples many receptors to adenylyl cyclase and is essential for hormone-stimulated cAMP generation. Previous mouse models with germ-line mutations in Gnas, the gene that encodes G_salpha had limited usefulness in trying to decipher the role of G_salpha pathways in specific tissues since only heterozygotes were viable and could be analyzed. Analysis was further complicated by the fact that G_salpha is imprinted expressed in many metabolically active tissues. G_salpha-floxed mice were generated so that the metabolic effects of G_salpha deficiency could be examined in specific tissues. Exon1, which is specific for G_salpha, was surrounded with loxP recombination sites. Liver-specific knockouts of G_salpha were obtained by mating the G_salpha-floxed mice with albumin promoter-Cre-transgenic mice. G_salpha exon1 was efficiently deleted. These mice have been used successfully to generate other tissue-specfic G_salpha knockout mice.