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Inhibition of Gαi2 – RGS Protein Interactions Protects the Heart from Ischemic Injury
Author(s) -
Mabe Nathaniel,
Thompson Corbin G,
Waterson Rachael E,
Kaur Kuljeet,
Talbot Jeffery N,
Neubig Richard R,
Rorabaugh Boyd R
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1085.3
Subject(s) - rgs2 , regulator of g protein signaling , g protein , gq alpha subunit , ischemic preconditioning , gs alpha subunit , gtpase activating protein , endogeny , medicine , pharmacology , ischemia , chemistry , microbiology and biotechnology , endocrinology , biology , receptor
Signaling through Gαi‐coupled receptors protects the heart from ischemic injury. The activity of Gαi is modulated by regulator of G protein signaling (RGS) proteins that terminate Gαi signaling by catalyzing the hydrolysis of Gαi‐bound GTP. We used knock‐in mice in which interactions between Gαi2 and RGS proteins are disrupted by a Gαi2G184S (GS) point mutation to determine whether interactions between Gαi2 and endogenous RGS proteins modulate Gαi‐mediated protection from ischemic injury. Hearts isolated from wildtype (+/+) mice and mice homozygous (GS/GS) or heterozygous (GS/+) for Gαi2G184S were subjected to 30 minutes ischemia and 2 hours reperfusion using the Langendorff method. Infarcts in GS/GS and GS/+ hearts were significantly smaller than those of +/+ hearts. Expression of Gαi2G184S had no effect on preischemic contractile function. However, postischemic recovery of contractile function was significantly enhanced in GS/GS and GS/+ hearts compared to +/+ hearts. The cardioprotective phenotype of GS/+ and GS/GS hearts was reversed by 5‐hydroxydecanoate indicating that inhibition of RGS‐ Gαi2 interactions protects the heart through a mechanism that requires mitochondrial K+ATP channels. These data suggest that RGS proteins may provide novel therapeutic targets to protect the heart from ischemic injury. (Supported by NIH R01 GM39561; AFPE, and the Bower, Bennet and Bennet Endowed Research Award).