The sarcoplasmic reticulum (SR) plays a critical role in mediating cardiac 
contractility and its function is abnormal in the diabetic heart. However, the 
mechanisms underlying SR dysfunction in the diabetic heart are not clear. 
Because protein phosphorylation regulates SR function, this study examined the 
phosphorylation state of phospholamban, a key SR protein that regulates SR 
calcium (Ca2+) uptake in the heart. Diabetes was induced in male Sprague-Dawley 
rats by an injection of streptozotocin (STZ; 65 mg kg(-1) i.v.), and the animals 
were humanely killed after 6 weeks and cardiac SR function was examined. 
Depressed cardiac performance was associated with reduced SR Ca2+-uptake 
activity in diabetic animals. The reduction in SR Ca2+-uptake was consistent 
with a significant decrease in the level of SR Ca2+-pump ATPase (SERCA2a) 
protein. The level of phospholamban (PLB) protein was also decreased, however, 
the ratio of PLB to SERCA2a was increased in the diabetic heart. Depressed SR 
Ca2+-uptake was also due to a reduction in the phosphorylation of PLB by the 
Ca2+-calmodulin-dependent protein kinase (CaMK) and cAMP-dependent protein 
kinase (PKA). Although the activities of the SR-associated 
Ca2+-calmodulin-dependent protein kinase (CaMK), cAMP-dependent protein kinase 
(PKA) were increased in the diabetic heart, depressed phosphorylation of PLB 
could partly be attributed to an increase in the SR-associated protein 
phosphatase activities. These results suggest that there is increased inhibition 
of SERCA2a by PLB and this appears to be a major defect underlying SR 
dysfunction in the diabetic heart.