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Am J Physiol Cell Physiol 283: C386-C395, 2002. doi:10.1152/ajpcell.00320.2001
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Vol. 283, Issue 2, C386-C395, August 2002

Targeted expression of activated Q227L Galpha s in vivo

Xi-Ping Huang1, Xiaosong Song1, Hsien-Yu Wang2, and Craig C. Malbon1

1 Department of Molecular Pharmacology and 2 Department of Physiology and Biophysics, Diabetes and Metabolic Diseases Research Program, University Medical Center, State University of New York at Stony Brook, Stony Brook, New York 11794

We report the creation of transgenic mice with an inducible, tissue-targeted expression of a constitutively active mutant form (Q227L) of Galpha s. Mice expressing activated Galpha 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 Galpha 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 Galpha i2 in tissues expressing constitutively active Galpha s that may act to rectify the impact of increased cAMP accumulation.

constitutively activated Galpha s; protein kinase A; regulatory subunits


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