title: Depressed levels of Ca2+-cycling proteins may underlie sarcoplasmic reticulum dysfunction in the diabetic heart.
abstract: In view of the depressed sarcoplasmic reticulum (SR) Ca2+-pump and Ca2+-release activities in the diabetic heart and the critical role of phosphorylation in regulating the SR function, we examined the status of Ca2+-calmodulin-dependent protein kinase (CaMK) and cAMP-dependent protein kinase (PKA)-mediated phosphorylations in the diabetic heart. Diabetes was induced in male Sprague-Dawley rats by an injection of streptozotocin (65 mg/kg i.v.), and the animals were killed 6 weeks later for assessment of the ventricular SR function. Depressed cardiac performance and SR Ca2+-uptake and -release activities in diabetic animals were accompanied by a significant decrease in the level of SR Ca2+-cycling proteins, such as ryanodine receptor, Ca2+-pump ATPase, and phospholamban. On the other hand, the CaMK- and PKA-mediated phosphorylations of these Ca2+-cycling proteins, the endogenous SR CaMK and PKA activities, and the endogenous SR and cytosolic phosphatase activities were increased in the diabetic heart. Treatment of 3-week diabetic animals with insulin partially or fully prevented the diabetes-induced changes in cardiac performance, SR Ca2+-uptake and -release activites, and SR protein content, whereas the diabetes-induced changes in SR CaMK- and PKA-mediated phosphorylations and activities, as well as phosphatase activities, were not significantly affected. These results suggest that the reduced content of the Ca2+-cycling proteins, unlike alterations in PKA and phosphatase activities, appear to be the major defect underlying SR dysfunction in the diabetic heart.
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Netticadan
authors.forename: R M
authors.initials: RM
authors.lastname: Temsah
authors.forename: A
authors.initials: A
authors.lastname: Kent
authors.forename: V
authors.initials: V
authors.lastname: Elimban
authors.forename: N S
authors.initials: NS
authors.lastname: Dhalla
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D006321:Heart / Q000503:physiopathology*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000502:physiology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D017868:Cyclic AMP-Dependent Protein Kinases; D010744:Phosphoric Monoester Hydrolases; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban