title: Gα(i2)-mediated protection from ischaemic injury is modulated by endogenous RGS proteins in the mouse heart.
abstract: OBJECTIVE
  Regulator of G protein signalling (RGS) proteins act as molecular 'off switches' that terminate G protein signalling by catalyzing the hydrolysis of Gα-bound GTP to GDP. Many different Gα(i)-coupled receptors have been implicated in the cardioprotective effects of ischaemic preconditioning. However, the role of RGS proteins in modulating cardioprotection has not been previously investigated. We used mice that were homozygous (GS/GS) or heterozygous (GS/+) for a mutation in Gα(i2) rendering it RGS-insensitive (G184S) to determine whether interactions between endogenous RGS proteins and Gα(i2) modulate Gα(i)-mediated protection from ischaemic injury.
  
  
  RESULTS
  Langendorff-perfused mouse hearts were subjected to 30 min global ischaemia and 2 h reperfusion. Infarcts in GS/GS (14.5% of area at risk) and GS/+ (22.6% of AAR) hearts were significantly smaller than those of +/+ hearts (37.2% of AAR) and recovery of contractile function was significantly enhanced in GS/GS and GS/+ hearts compared with +/+ hearts. The cardioprotective phenotype was not reversed by wortmannin or U0126 but was reversed by 5-hydroxydecanoic acid and HMR 1098, indicating that RGS-insensitive Gα(i2) protects the heart through a mechanism that requires functional ATP-dependent potassium channels but does not require acute activation of extracellular-regulated kinase or Akt signalling pathways.
  
  
  CONCLUSIONS
  This is the first study to demonstrate that Gα(i2)-mediated cardioprotection is suppressed by RGS proteins. These data suggest that RGS proteins may provide novel therapeutic targets to protect the heart from ischaemic injury.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, 525 South Main Street, Ada, OH 45810, USA.
authors.forename: Rachael E
authors.initials: RE
authors.lastname: Waterson
authors.forename: Corbin G
authors.initials: CG
authors.lastname: Thompson
authors.forename: Nathaniel W
authors.initials: NW
authors.lastname: Mabe
authors.forename: Kuljeet
authors.initials: K
authors.lastname: Kaur
authors.forename: Jeffery N
authors.initials: JN
authors.lastname: Talbot
authors.forename: Richard R
authors.initials: RR
authors.lastname: Neubig
authors.forename: Boyd R
authors.initials: BR
authors.lastname: Rorabaugh
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D016018:Least-Squares Analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010477:Perfusion; D010641:Phenotype; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D020710:RGS Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D054086:KATP Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D020710:RGS Proteins; C117780:mitochondrial K(ATP) channel; D051960:GTP-Binding Protein alpha Subunit, Gi2; C498016:Gnai2 protein, mouse