Many important cellular processes are controlled via stimulation (or inhibition) of signal transduction systems, among which heptahelical G protein–coupled receptors (GPCRs) figure prominently. A classical example in cardiac myocytes is the β-adrenergic receptor (β-AR) cascade (see Figure, panel A), which leads to positive inotropic and lusitropic effects.1 Occupation of the β-ARs by an agonist activates a GTP binding protein (Gs), such that the α subunit dissociates and activates adenylyl cyclase (AC), thereby producing cAMP. The increase in cAMP leads to the dissociation of the regulatory and catalytic subunits of protein kinase A (PKA). PKA can be tethered near its substrates by an A-kinase anchoring protein (AKAP). The PKA catalytic subunit phosphorylates several key myocyte proteins involved in excitation-contraction (E-C) coupling, including the L-type Ca2+ channel, phospholamban (PLB), ryanodine receptor (RyR), myosin binding protein C, and troponin I (TnI). These effects produce PKA-dependent increases in Ca2+ current ( I Ca), sarcoplasmic reticulum (SR) Ca2+ uptake and release, as well as a desensitization of the myofilaments to Ca2+. The net result is the characteristic positive inotropic and lusitropic effects of β-AR activation in cardiac myocytes. A, Local β-AR signaling cascade in cardiac myocytes. B, GLP-1 signaling cascade. In this pathway, cAMP may activate glycolysis but cannot activate I Ca, PLB, or TnI phosphorylation. Epi indicates epinephrine; PFK, phosphofructokinase; and ATPase, SR Ca2+-ATPase (see text for other abbreviations). The stimulatory effects of GPCR activation can be inhibited at several levels. The receptor can be desensitized by G protein receptor kinases (eg, β-ARK) and arrestins.2 The activation of AC by Gsα can be antagonized by an inhibitory G protein (Gi), which can be activated by muscarinic receptors (and may also be coactivated during β2-AR activation).3–5 The effects of …