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Targeted expression of activated Q227L G(alpha)(s) in vivo.

We report the creation of transgenic mice with an inducible, tissue-targeted expression of a constitutively active mutant form (Q227L) of G(alpha)(s). Mice expressing activated G(alpha)(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 G(alpha)(i2). The reduction in kinase activity coincided with >50% increase in the expression of RIalpha and RIIalpha 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 G(alpha)(i2) in tissues expressing constitutively active G(alpha)(s) that may act to rectify the impact of increased cAMP accumulation.