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(Circulation Research. 2004;94:1133.)
© 2004 American Heart Association, Inc.

Integrative Physiology

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

Haiyan Tong, Howard A. Rockman, Walter J. Koch, Charles Steenbergen, Elizabeth Murphy

From the Laboratory of Signal Transduction (H.T., E.M.), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, and Department of Medicine, Cell Biology and Genetics (H.A.R.), Department of Surgery (W.J.K.), and Department of Pathology (H.T., C.S.), Duke University Medical Center, Durham, NC. W.J.K. is presently at the Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pa.

Correspondence to Dr Elizabeth Murphy, NIEHS, NIH, 111 Alexander Dr, Research Triangle Park, NC 27709. E-mail murphy1{at}niehs.nih.gov

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 Gß-sequestering peptide, ßARKct (TG ßARKct mice), to test whether the protection of PC is Gß-dependent. To test the role of G_i protein, we used wild-type mice pretreated with the G_i 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 ßARKct mice. To determine the mechanism of Gß-induced protection in PC, we investigated one of the downstream targets of Gß, the PI3K/p70S6K pathway. PC-induced phosphorylation of p70S6K was not blocked in TG ßARKct hearts; therefore, we investigated other targets of Gß. Recent studies suggest a role for Gß in GPCR internalization. We found that ßARKct, a specific PI3K inhibitor wortmannin, and bafilomycin A₁, which all block receptor recycling, all blocked the protective effect of PC. To additionally test whether PI3K is involved in PC-activated receptor internalization and endosomal signaling, we used TG mice with cardiac-specific overexpression of a catalytically inactive mutant PI3K, which disrupts the recruitment of functional PI3K to agonist-activated GPCRs in vivo. We found that the catalytically inactive mutant of PI3K blocks the protection of PC. In summary, these data suggest the novel finding that the cardioprotective effect of PC requires receptor internalization.

Key Words: Gß • phosphatidylinositol 3-kinase • transgenic mice • isolated heart • ischemic preconditioning

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