G Protein-Coupled Receptor Internalization Signaling Is Required for Cardioprotection in Ischemic Preconditioning

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Abstract
The present study is designed to explore the role of G protein-coupled receptors (GPCRs) in the protection afforded by ischemic preconditioning (PC). We used TG mice with cardiac-specific overexpression of a Gβγ-sequestering peptide, βARKct (TG βARKct mice), to test whether the protection of PC is Gβγ-dependent. To test the role of Gi protein, we used wild-type mice pretreated with the Gi inhibitor pertussis toxin. Recovery of left ventricular developed pressure and infarct size were measured as indices of protection. PC induced protection in wild-type mice, but this protection was blocked by pertussis toxin treatment and was also blocked in TG βARKct mice. To determine the mechanism of Gβγ-induced protection in PC, we investigated one of the downstream targets of Gβγ, the PI3K/p70S6K pathway. PC-induced phosphorylation of p70S6K was not blocked in TG βARKct hearts; therefore, we investigated other targets of Gβγ. Recent studies suggest a role for Gβγ in GPCR internalization. We found that βARKct, a speci...