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Phosphodiesterase 4 and Phosphatase 2A Differentially Regulate cAMP/Protein Kinase A Signaling for Cardiac Myocyte Contraction under Stimulation of β₁ Adrenergic Receptor

Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, Illinois

Activation of the β adrenergic receptor (βAR) induces a tightly controlled cAMP/protein kinase A (PKA) activity to ensure an agonist dose-dependent and saturable contraction response in animal heart. We have found that stimulation of β₁AR by isoproterenol induces maximal contraction responses at the dose of 1 µM in cardiac myocytes; however, cAMP accumulation continues to increase with higher agonist concentrations. Dose-dependent cAMP accumulation is tightly controlled by negative regulator phosphodiesterase 4 (PDE4) that hydrolyzes cAMP. At 1 nM isoproterenol, cAMP accumulation is minimal because of the hydrolysis of cAMP by PDE4, which leads to a small increase in PKA phosphorylation of phospholamban and troponin I (TnI), and contraction responses. Inhibition of PDE4 activity with rolipram enhances cAMP accumulation, yields maximal PKA phosphorylation of phospholamban and TnI, and myocyte contraction responses. In contrast, at 10 µM isoproterenol, despite the negative effect of PDE4, cAMP accumulation is sufficient for maximal PKA phosphorylation of phospholamban and TnI. Inhibition of PDE4 with rolipram enhances cAMP accumulation, but not PKA phosphorylation and contraction responses. It is interesting that activities of both PKA and protein phosphatase 2A (PP2A) are enhanced under β₁AR activation with 10 µM isoproterenol, and PP2A is recruited to PKA/A kinase-anchoring protein complex. Inhibition of PP2A with okadaic acid further enhances the phosphorylation of phospholamban and TnI as well as contraction responses induced by 10 µM isoproterenol. Therefore, PP2A plays a key role in limiting PKA phosphorylation of phospholamban and TnI for myocyte contraction responses under β₁AR stimulation.

Address correspondence to: Dr. Yang Xiang, Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, 523 Burrill Hall, MC-114, 407 S. Goodwin Ave., Urbana, IL 61801. E-mail: kevinyx{at}illinois.edu

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				D. Soto, V. De Arcangelis, J. Zhang, and Y. Xiang Dynamic Protein Kinase A Activities Induced by {beta}-Adrenoceptors Dictate Signaling Propagation for Substrate Phosphorylation and Myocyte Contraction Circ. Res., March 27, 2009; 104(6): 770 - 779. [Abstract] [Full Text] [PDF]