GRKs

G protein-coupled receptor kinases (GRKs) are a family of serine/threonine kinases that phosphorylate activated G protein-coupled receptors (GPCRs). This phosphorylation promotes the binding of arrestin proteins, which uncouples the receptor from G proteins and facilitates receptor internalization. In addition to desensitization, arrestin-bound GPCRs can initiate alternative signaling pathways, making GRKs central regulators of GPCR signaling dynamics.

In humans, seven GRKs have been described: GRK1 through GRK7. GRK1 and GRK7 are classified as visual GRKs expressed in photoreceptor cells and regulate signaling in the retina. The remaining GRKs—GRK2, GRK3, GRK4, GRK5, and GRK6—are more broadly expressed and regulate signaling from a wide range of GPCRs, including receptors for catecholamines, dopamine, opioids, muscarinic ligands, and chemokines. GRK2 and GRK3 are often referred to as beta-adrenergic receptor kinases due to their prominent roles in adrenergic signaling.

Structural and regulatory features: GRKs share a catalytic kinase domain and typically have additional regulatory regions that control localization and activity. Notably, GRK2 and GRK3 contain an N-terminal regulator of G protein signaling (RGS)–like domain and a C-terminal pleckstrin homology (PH) domain that promotes membrane association through lipid interactions. Other GRKs have distinct N- or C-terminal elements that influence their subcellular distribution and receptor preference.

Physiological and clinical relevance: GRKs regulate signaling in many tissues and physiological processes, including cardiovascular function, sensory perception, and CNS signaling. Altered GRK expression or activity has been linked to disease states such as heart failure and retinal disorders, and they are active areas of research for therapeutic modulation of GPCR signaling.

Research and therapeutic context: Researchers study GRK structure, substrate specificity, and regulation through biochemical, cellular, and animal models. Targeting GRKs to tune GPCR responses offers potential strategies for treating diseases driven by GPCR dysregulation, though achieving selectivity remains a challenge.