G protein-coupled receptor kinase 3 (GRK3)

G protein-coupled receptor kinase 3 (GRK3) is an enzyme in the serine/threonine protein kinase family, encoded by the ADRBK2 gene in humans, and is also known as beta-adrenergic receptor kinase 2 (βARK-2). GRK3 plays a critical role in regulating the signaling of activated G protein-coupled receptors (GPCRs) by phosphorylating them, which promotes arrestin binding. This process leads to rapid receptor desensitization, internalization, and trafficking, thereby controlling the amplitude and duration of GPCR signaling. GRK3 serves as a negative regulator of GPCR activity, particularly in pathways involving chemokine receptors such as CXCR4, and adrenergic receptors in the heart and other tissues. It is broadly expressed but is especially prominent in the nervous, cardiovascular, and immune systems. Aberrations in GRK3 expression or function have been implicated in several human diseases, including certain cancers, neuropsychiatric disorders, cardiovascular conditions, immune deficiencies, and bone diseases[1][5][6][7]. No direct therapeutic inhibitors or activators are approved for clinical use as of 2024, but its regulatory axis with GPCRs makes it an emerging target of interest in drug discovery.

Other names

Beta-adrenergic receptor kinase 2βARK-2BARK2ADRBK2

Inhibition or modulation of GRK3 can increase GPCR signaling by preventing receptor desensitization/internalization, potentially enhancing or prolonging signaling of involved GPCRs (e.g., α1-adrenergic receptor, CXCR4) Drugs that bias GPCR phosphorylation patterns may selectively enhance or mitigate GRK3-dependent signaling or desensitization