both to Gαs and to the inhibitory G protein (Gαi), which functions, in part, to diminish adenylyl cyclase activity and subsequent cAMP levels (Figure 1). The ß1-adrenergic receptor constitutes 70% to 80% of the total ß-receptor population on normal adult cardiac myocytes, so that catecholamine stimulation primarily leads to an increase in cAMP. 13 However, the cardiomyopathic heart exhibits a downregulation of ß1-adrenergic receptors so that the ratio of ß1 to ß2 is closer to 50: 50, ultimately increasing Gαi signaling and diminishing cAMP-mediated responses. 13 With respect to regulation of myocyte contractility, ß-receptor–mediated activation of Gαs can also directly couple to the voltage-dependent L-type calcium channel in the sarcolemma, enhancing calcium influx. 14, 15 Once generated, cAMP plays a preeminent role in regulating myocyte contractility through the direct activation of the cAMP-dependent protein kinase A (PKA). PKA in turn directly phosphorylates the L-type calcium channel, the ryanodine receptor, and phospholamban, which together coordinate significant increases in calcium inotropy16(Figure 1). Phospholamban is a negative regulator of the sarco (endo-) plasmic reticulum Ca (2)-ATPase 2 (SERCA2) within the sarcoplasmic reticulum (SR). PKA-mediated phosphorylation of phospholamban at Ser16 causes its disassociation from SERCA2, permitting maximal calcium ATPase activity and maximal SR loading, which in turn generates larger action potentials during systole. 16 cAMP-dependent PKA activation further augments the contractile response by directly phosphorylating the type-1 protein phosphatase (PP1) inhibitor-1 protein, thus reducing PP1 activity that normally functions to remove the phosphate at Ser16 in phospholamban16(Figure 1). Finally, PKA-dependent phosphorylation of contractile proteins such as troponin I and myosin binding protein C also enhances the relaxation cycling of myofilaments17 (Figure 1). Thus, ß-adrenergic receptors mediate acute contractile alterations through only a handful of downstream “nodal” regulatory proteins in the heart. Manipulating the expression or activity of these nodal regulatory proteins profoundly influences the contractile function of the heart and its propensity toward cardiomyopathy after injury, as discussed below.