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Background  Regulator of G protein signaling (RGS) proteins suppress G protein coupled receptor signaling by catalyzing the hydrolysis of Gα-bound guanine nucleotide triphosphate. Transgenic mice in which RGS-mediated regulation of Gα i2  is lost (RGS insensitive Gα i2  G184S ) exhibit beneficial (protection against ischemic injury) and detrimental (enhanced fibrosis) cardiac phenotypes. This mouse model has revealed the physiological significance of RGS/Gα i2  interactions. Previous studies of the Gα i2  G184S  mutation used mice that express this mutant protein throughout their lives. Thus, it is unclear whether these phenotypes result from chronic or acute Gα i2  G184S  expression. We addressed this issue by developing mice that conditionally express Gα i2  G184S .    Methods  Mice that conditionally express RGS insensitive Gα i2  G184S  were generated using a floxed minigene strategy. Conditional expression of Gα i2  G184S  was characterized by reverse transcription polymerase chain reaction and by enhancement of agonist-induced inhibition of cAMP production in isolated cardiac fibroblasts. The impact of conditional RGS insensitive Gα i2  G184S  expression on ischemic injury was assessed by measuring contractile recovery and infarct sizes in isolated hearts subjected to 30 min ischemia and 2 hours reperfusion.    Results  We demonstrate tamoxifen-dependent expression of Gα i2  G184S , enhanced inhibition of cAMP production, and cardioprotection from ischemic injury in hearts conditionally expressing Gα i2  G184S . Thus the cardioprotective phenotype previously reported in mice expressing Gα i2  G184S  does not require embryonic or chronic Gα i2  G184S  expression. Rather, cardioprotection occurs following acute (days rather than months) expression of Gα i2  G184S .    Conclusions  These data suggest that RGS proteins might provide new therapeutic targets to protect the heart from ischemic injury. We anticipate that this model will be valuable for understanding the time course (chronic versus acute) and mechanisms of other phenotypic changes that occur following disruption of interactions between Gα i2  and RGS proteins.

Conditional disruption of interactions between Gαi2 and regulator of G protein signaling (RGS) proteins protects the heart from ischemic injury