... the human heart, which further accelerate cardiac pathology. 6,9,11 In the heart, NE binds to the??1B and ?1AR, while epinephrine binds to the ?1- and ?2AR.11,12 Approximately 75% of the ?AR are ?1AR.11,13 These ?AR are primarily coupled with heterotrimeric G proteins, Gs, to stimulate adenylyl cyclase (AC). This coupling is followed by a whole cascade of signaling pathways, which can further regulate cardiac contractility and heart rate.11,14 When these ARs are occupied, they become substrates for regulation via G protein-coupled receptor kinases (GRKs).11,15 GRKs further phosphorylate the activated AR, which allows binding of ?-arrestins.11 This binding hinders the coupling to G proteins, and thus desensitizes and uncouples the signal.11 GRK2 is the principle GRK involved in the intracellular signaling of the heart and it does play a critical role, especially in HF.11,16 Figure 1: Model depicting the desensitization of the ?2-adrenergic receptor, as prototypic system in the regulation of GPCRs.54 Importantly, in ...

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