title: Diabetes-related defects in sarcoplasmic Ca2+ release are prevented by inactivation of G(alpha)11 and G(alpha)q in murine cardiomyocytes.
abstract: Neurohumoral stimulation of Gq-coupled receptors has been proposed as a central mechanism in the pathogenesis of diabetic heart disease. The resulting contractile dysfunction is closely related to abnormal intracellular Ca(2+) handling with functional defects of the sarcoplasmic reticulum (SR). The present study was therefore designed to determine the role of G(q)-protein signaling via G(alpha)(11) and G(alpha)(q) in diabetes for the induction of functional and structural changes in the Ca(2+) release complex of the SR. An experimental type 1-diabetes was induced in wild type, G(alpha)(11) knockout, and G(alpha)(11/q)-knockout mice by injection of streptozotocin. Cardiac morphology and function was assessed in vivo by echocardiography. SR Ca(2+) leak was tested in vitro based on a (45)Ca(2+) assay and protein densities as well as gene expression of ryanodine receptor (RyR2), FKBP12.6, sorcin, and annexin A7 were analyzed by immunoblot and RT-PCR. In wild type animals 8 weeks of diabetes resulted in cardiac hypertrophy and SR Ca(2+) leak was increased. In addition, diabetic wild type animals showed reduced protein levels of FKBP12.6 and annexin A7. In G(alpha)(11)- and G(alpha)(11/q)-knockout animals, however, SR Ca(2+) release and cardiac phenotype remained unchanged upon induction of diabetes. Densities of the proteins that we presently analyzed were also unaltered in G(alpha)(11)-knockout mice. G(alpha)(11/q)-knockout animals even showed increased expression of sorcin and annexin A7. Thus, based on the present study we suggest a signaling pathway via the G(q)-proteins, G(alpha)(11) and G(alpha)(q), that could link increased neurohumoral stimulation in diabetes with defective RyR2 channel function by regulating protein expression of FKBP12.6, annexin A7, and sorcin.
authors.affiliation: Department of Internal Medicine III, University of Cologne, Kerpener Str 62, 50937 Cologne, Germany.
authors.forename: Dieter Paul
authors.initials: DP
authors.lastname: Hoyer
authors.forename: Sabine
authors.initials: S
authors.lastname: Grönke
authors.forename: Konrad F
authors.initials: KF
authors.lastname: Frank
authors.forename: Klaus
authors.initials: K
authors.lastname: Addicks
authors.forename: Nina
authors.initials: N
authors.lastname: Wettschureck
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.forename: Erland
authors.initials: E
authors.lastname: Erdmann
authors.forename: Hannes
authors.initials: H
authors.lastname: Reuter
mesh_terms: D000818:Animals; D017310:Annexin A7 / Q000032:analysis; D002118:Calcium / Q000378:metabolism*; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism; D048909:Diabetes Complications / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D006331:Heart Diseases / Q000209:etiology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000032:analysis; D019837:Ryanodine Receptor Calcium Release Channel / Q000032:analysis; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000032:analysis
chemical_list: D017310:Annexin A7; D011506:Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B; D002118:Calcium