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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Publikationen des W. G. Kerckhoff-Instituts     Display Documents

ID: 559713.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Publikationen des W. G. Kerckhoff-Instituts
Diabetes-related defects in sarcoplasmic Ca2+ release are prevented by inactivation of G(alpha)11 and G(alpha)q in murine cardiomyocytes
Authors:Hoyer, D. P.; Gronke, S.; Frank, K. F.; Addicks, K.; Wettschureck, N.; Offermanns, S.; Erdmann, E.; Reuter, H.
Title of Journal:Mol Cell Biochem
Issue / Number:1-2
Start Page:235
End Page:44
Audience:Not Specified
Abstract / Description: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.
Free Keywords:Animals; Annexin A7/analysis; Calcium/*metabolism; Cardiomegaly/etiology/metabolism; Diabetes Complications/*metabolism; Diabetes Mellitus, Experimental/*metabolism/pathology; GTP-Binding Protein alpha Subunits, Gq-G11/*metabolism; Heart Diseases/etiology/metabolism; Mice; Mice, Knockout; Myocytes, Cardiac/*metabolism/pathology; Proteins/analysis; Ryanodine Receptor Calcium Release Channel/analysis; Sarcoplasmic Reticulum/*metabolism; Tacrolimus Binding Proteins/analysis
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:Department of Internal Medicine III, University of Cologne, Kerpener Str 62, 50937 Cologne, Germany.
Identifiers:ISSN:1573-4919 (Electronic) 0300-8177 (Linking)
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