Transgenic mice were created with cardiac-specific overexpression of the 1-adrenergic receptor kinase-1 (MARK1) or a PARK inhibitor. Animals overexpressing HARK1 demonstrated attenuation of isoproterenol-stimulated left ventricular contractility in vivo, dampening of myocardial adenylyl cyclase activity, and reduced functional coupling of 1-adrenergic receptors. Conversely, mice expressing the PARK inhibitor displayed enhanced cardiac contractility in vivo with or without isoproterenol. These animals demonstrate the important role of PARK in modulating in vivo myocardial function. Because increased amounts of PARK1 and diminished cardiac 1-adrenergic responsiveness characterize heart failure, these animals may provide experimental models to study the role of PARK in heart disease.W-adrenergic receptors (PARs) are the primary myocardial targets of the sympathetic neurotransmitter norepinephrine and the adrenal hormone epinephrine. Human myocardium contains 13I-and 132AR subtypes with the PI3AR being most abundant (1). Activation of PARs (PI and P2) in the heart by agonist binding causes stimulation of adenylyl cyclase, increased intracellular concentrations of adenosine 3',5 '-monophosphate (cAMP), and increased cytosolic calcium transients resulting in positive chronotropy and inotropy (increased rate and force of contraction). As is true for most heterotrimeric guanosine triphosphate (GTP) binding protein (G protein)-coupled receptors, prolonged exposure of PARs to agonist results in a rapid decrease in responsiveness. Agonist-dependent desensitization can be initiated by phosphorylation of activated receptors by members of the G protein-coupled receptor kinase (GRK) family (2). The P3-adrenergic receptor kinase-1 (PARKI) is a GRK that specifically phosphorylates activated P13 -(3) and P2ARs (2) in in vitro assays. In the case of the 13AR, these assays used cultured mammalian cells or highly purified membrane preparations

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