Targeted expression of activated Q227L Gα_s in vivo

We report the creation of transgenic mice with an inducible, tissue-targeted expression of a constitutively active mutant form (Q227L) of Gα_s. Mice expressing activated Gα_s in fat tissue, liver, and skeletal muscle displayed normal body mass and blunted glucose metabolism. cAMP accumulation in adipose tissue was increased in the basal state, but far less than would be expected. Marked adaptation to elevated cAMP levels occurred, leading to an increase in total cAMP-specific phosphodiesterase activity, a 50% decline in cAMP-dependent protein kinase (protein kinase A) activity, and an increased expression of Gα_i2. The reduction in kinase activity coincided with >50% increase in the expression of RIα and RIIα regulatory subunits of protein kinase A, with no change in the amount of catalytic subunit. These data demonstrate the existence of adaptive responses of protein kinase A, phosphodiesterase, and Gα_i2 in tissues expressing constitutively active Gα_s that may act to rectify the impact of increased cAMP accumulation.