ltered cellular Ca 2+ handling plays a key role in the pathophysiology of heart failure. A typical aspect of failing heart cells is a decrease in the ability to load Ca 2+ in the sarcoplasmic reticulum (SR), which results in a decreased amplitude and slowed rate of decay of Ca 2+ transients (CaTs), and in some cases, an increased diastolic intracellular Ca 2+ concentration ([Ca 2+ ]i). 1,2 The reduction in SR Ca 2+ loading could be ascribed to a decrease in Ca 2+ re-uptake by the SR Ca 2+

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... (SERCA), and increases in the SR Ca 2+ leak and the Ca 2+ extrusion via Na + /Ca 2+ exchanger. 3 Editorial p 1018 In the heart, the activity of SERCA is inhibited by the associated membrane protein, phospholamban (PLB), in its un-phosphorylated state. However, once Ser-16 and/or Thr-17 of PLB is phosphorylated, this inhibition is alleviated. Ser-16 and Thr-17 are phosphorylated by protein kinase A Background: An increase in cytosolic protein phosphatases (PPs) de-phosphorylates phospholamban, decreasing the Ca 2+ uptake of the sarcoplasmic reticulum (SR). The effects of PP inhibitors on cellular Ca 2+ handling were investigated. Methods and Results: Twitch Ca 2+ transients (CaTs) and cell shortening were measured in intact rat cardiac myocytes, and caffeine-induced Ca 2+ transients (CaffCaTs) and Ca 2+ sparks were studied in saponin-permeabilized cells. Calyculin A augmented isoproterenol-induced increases in CaTs and cell shortening without altering the diastolic [Ca 2+ ]i and twitch [Ca 2+ ]i decay. The protein kinase A catalytic subunit (PKAcat) increased the peak of CaffCaTs between 5 and 50 U/ml, and the addition of inhibitor-1 (I-1) augmented the increase. PKAcat increased Ca 2+ spark frequency and the addition of I-1 increased it further. PKAcat at 50 U/ml amplified the peak and prolonged the duration of Ca 2+ sparks, whereas the addition of I-1 did not alter them. An abrupt inhibition of SR Ca 2+ uptake following exposure to PKAcat caused a gradual decrease in Ca 2+ spark frequency, but the addition of I-1 did not accelerate the decline of Ca 2+ spark frequency or CaffCaTs. Conclusions: Inhibition of PPs augmented the inotropic effect of isoproterenol. Specific inhibition of PP1 could stimulate the Ca 2+ uptake of the SR with less significant effects on the Ca 2+ release. (Circ J 2009; 73: 1133 -1140