Abstract
Protein Kinase A (PKA) is the major mediator of β-adrenergic (βAR) regulation of cardiac contractility but other mediators (e.g., EPAC) have also been suggested. Reduced PKA basal activity and activation are linked to cardiac diseases. However, the roles of PKA in cardiac physiology and pathology have not been clearly defined because it has been difficult to knockout all expressed PKA catalytic subunit genes in cardiomyocytes. We ablated PKA activity and activation in cardiomyocytes by expressing a PKA inhibitor peptide (PKAi-GFP) in cardiomyocytes in transgenic (TG) mice. We made novel discoveries that: (1) Basal PKA-mediated phosphorylation was reduced for proteins in myofilaments and longitudinal SR but not for proteins in subsarcolemmal and dyadic spaces in PKAi TG hearts, suggesting basal PKA activity is different in individual cellular compartments; (2) PKAi increased the expression of CaMKII, the L-type Ca 2+ channel β subunits and current, but decreased CaMKII phosphorylation; (3) These changes resulted in significantly enhanced myofilament Ca 2+ sensitivity with prolonged contraction and relaxation, decreased myocyte Ca 2+ transient decay rate but enhanced myocyte contractility. (4) PKA inhibition fully abolishes the increases of heart rate, and cardiac and myocyte contractility by a β-adrenergic agonist (isoproterenol, ISO), showing a surprising dominant role of PKA in heart rate regulation and a minimal role of PKA-independent βAR signaling in regulating cardiac function; (5) The increased phosphorylation of proteins mediated by PKA and CaMKII after ISO was prevented by PKAi because increased PKA and CaMKII activation by ISO was eliminated by PKAi in vivo and in vitro . (6) PKAi TG mice maintained partial exercise capability by enhancing basal cardiac function, vascular constriction and ventricular filling (i.e., preload) during βAR stimulation. These features resemble some of the characteristics of diseased hearts. However, PKAi TG mice did not show any cardiac functional or structural abnormalities during the 1-year study period. In conclusion, PKA is the essential mediator of acute βAR regulation of cardiac function and exercise capacity, but the loss of PKA basal activity and activation by βAR agonists do not cause cardiac disease.
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