| First Author | Parra S | Year | 2014 |
| Journal | BMC Pharmacol Toxicol | Volume | 15 |
| Pages | 29 | PubMed ID | 24899231 |
| Mgi Jnum | J:217517 | Mgi Id | MGI:5614291 |
| Doi | 10.1186/2050-6511-15-29 | Citation | Parra S, et al. (2014) Conditional disruption of interactions between Galphai2 and regulator of G protein signaling (RGS) proteins protects the heart from ischemic injury. BMC Pharmacol Toxicol 15:29 |
| abstractText | BACKGROUND: Regulator of G protein signaling (RGS) proteins suppress G protein coupled receptor signaling by catalyzing the hydrolysis of Galpha-bound guanine nucleotide triphosphate. Transgenic mice in which RGS-mediated regulation of Galphai2 is lost (RGS insensitive Galphai2G184S) exhibit beneficial (protection against ischemic injury) and detrimental (enhanced fibrosis) cardiac phenotypes. This mouse model has revealed the physiological significance of RGS/Galphai2 interactions. Previous studies of the Galphai2G184S mutation used mice that express this mutant protein throughout their lives. Thus, it is unclear whether these phenotypes result from chronic or acute Galphai2G184S expression. We addressed this issue by developing mice that conditionally express Galphai2G184S. METHODS: Mice that conditionally express RGS insensitive Galphai2G184S were generated using a floxed minigene strategy. Conditional expression of Galphai2G184S 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 Galphai2G184S 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 Galphai2G184S, enhanced inhibition of cAMP production, and cardioprotection from ischemic injury in hearts conditionally expressing Galphai2G184S. Thus the cardioprotective phenotype previously reported in mice expressing Galphai2G184S does not require embryonic or chronic Galphai2G184S expression. Rather, cardioprotection occurs following acute (days rather than months) expression of Galphai2G184S. 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 Galphai2 and RGS proteins. |
