Figure 1.

Summary diagram of the predominant canonical and non-canonical activities of GRK2 that alter cardiac physiology and disease progression. (1) The historically classical function of GRK2 in regulating GPCR activity wherein phosphorylation of β₁ARs triggers desensitization to attenuate downstream effector signaling. (2) Phosphorylation of non-GPCR targets HDAC6, tubulin, synucleins, and ezrin for GRK2-mediated regulation of cytoskeletal rearrangements and cell migration. (3) GRK2 as a negative regulator of insulin-dependent glucose uptake and insulin signaling by an unknown mechanism. (4) GRK2-mediated recruitment of PI3K to the membrane for enhanced internalization of agonist bound βARs and less well understood interactions for regulating endocytosis. (5) Selective interaction of the GRK2 N-terminal peptide βARKrgs, but not full-length GRK2, with Gαq in the heart, thereby inhibiting activation of Gαq-coupled GPCR effectors to reduce hypertrophic signaling. (6) GRK2 localization to the mitochondrial outer membrane, where phosphorylation of non-GPCR targets reduces the induction of vital cell survival pathways such as Akt and nitric oxide, thereby altering mitochondrial biogenesis and cell survival.