Thus the GRK/arrestin system serves as a complex signaling switch for G protein-coupled receptors.

[7] GRK2 and the closely related GRK3 phosphorylate receptors at sites that encourage arrestin-mediated receptor desensitization, internalization and trafficking rather than arrestin-mediated signaling (in contrast to GRK5 and GRK6, which have the opposite effect).

[10][11] GRK2 is expressed broadly in tissues, but generally at higher levels than the related GRK3.

[12] GRK2 was originally identified as a protein kinase that phosphorylated the β2-adrenergic receptor, and has been most extensively studied as a regulator of adrenergic receptors (and other GPCRs) in the heart, where it has been proposed as a drug target to treat heart failure.

[13][14] Strategies to inhibit GRK2 include using small molecules (including Paroxetine and Compound-101) and using gene therapy approaches utilizing regulatory domains of GRK2 (particularly overexpressing the carboxy terminal pleckstrin-homology (PH) domain that binds the G protein βγ-subunit complex and inhibits GRK2 activation (often called the “βARKct”), or just a peptide from this PH domain).