Diabetes-related defects in sarcoplasmic Ca2+ release are prevented by inactivation of G(alpha)11 and G(alpha)q in murine cardiomyocytes.
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.
Hoyer
Dieter Paul
DP
Department of Internal Medicine III, University of Cologne, Kerpener Str 62, 50937 Cologne, Germany.
Grönke
Sabine
S
Frank
Konrad F
KF
Addicks
Klaus
K
Wettschureck
Nina
N
Offermanns
Stefan
S
Erdmann
Erland
E
Reuter
Hannes
H
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
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