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

BMC Pharmacology and Toxicology

Richard R Neubig¹  Boyd R Rorabaugh³  Kuljeet Kaur²  Susan M Wade²  Raelene A Charbeneau²  Xinyan Huang²  Sergio Parra² 

[1] Department of Pharmacology and Toxicology, B440 Life Sciences, Michigan State University, 1355 Bogue St, East Lansing, MI 48824, USA;Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, USA;Department of Pharmaceutical and Biomedical Sciences, Ohio Northern University College of Pharmacy, Ada, OH 45810, USA

关键词: RGS;    Regulator of G protein signaling;    cAMP inhibition;    Mutation;    Cre-LoxP;    Ischemia-reperfusion;    G protein coupled receptors;   

Others  :  797488
DOI  :  10.1186/2050-6511-15-29

 received in 2014-02-18, accepted in 2014-05-28,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Parra et al.; licensee BioMed Central Ltd.

【 图 表 】

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