GRK5
Description
The GRK5 (G protein-coupled receptor kinase 5) is a protein-coding gene located on chromosome 10.
G protein-coupled receptor kinase 5 (GRK5) is a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases, and is most highly similar to GRK4 and GRK6. The protein phosphorylates the activated forms of G protein-coupled receptors to regulate their signaling.
== Function == G protein-coupled receptor kinases phosphorylate activated G protein-coupled receptors, which promotes the binding of an arrestin protein to the receptor. Arrestin binding to phosphorylated, active receptor prevents receptor stimulation of heterotrimeric G protein transducer proteins, blocking their cellular signaling and resulting in receptor desensitization. Arrestin binding also directs receptors to specific cellular internalization pathways, removing the receptors from the cell surface and also preventing additional activation. Arrestin binding to phosphorylated, active receptor also enables receptor signaling through arrestin partner proteins. Thus the GRK/arrestin system serves as a complex signaling switch for G protein-coupled receptors. GRK5 and the closely related GRK6 phosphorylate receptors at sites that encourage arrestin-mediated signaling rather than arrestin-mediated receptor desensitization, internalization and trafficking (in contrast to GRK2 and GRK3, which have the opposite effect). This difference is one basis for pharmacological biased agonism (also called functional selectivity), where a drug binding to a receptor may bias that receptor's signaling toward a particular subset of the actions stimulated by that receptor. GRK5 is widely expressed throughout the body, but with notably high expression in the lung, heart and placenta, with widespread expression at lower levels.
GRK5 is a serine/threonine kinase that preferentially phosphorylates the activated forms of various G-protein-coupled receptors (GPCRs). This phosphorylation triggers beta-arrestin-mediated receptor desensitization, internalization, and signaling events, ultimately leading to downregulation of the receptor. GRK5 phosphorylates a wide range of GPCRs, including adrenergic receptors, muscarinic acetylcholine receptors (specifically the Gi-coupled M2/M4 subtypes), dopamine receptors, and opioid receptors. Beyond GPCRs, GRK5 also phosphorylates several other substrates: Hsc70-interacting protein/ST13, TP53/p53, HDAC5, and arrestin-1/ARRB1. The phosphorylation of ARRB1 by GRK5 inhibits G-protein independent MAPK1/MAPK3 signaling downstream of 5HT4-receptors. Phosphorylation of HDAC5, a repressor of myocyte enhancer factor 2 (MEF2), results in the nuclear export of HDAC5, allowing MEF2-mediated transcription. Phosphorylation of TP53/p53, a critical tumor suppressor, inhibits TP53/p53-mediated apoptosis. Phosphorylation of ST13 regulates the internalization of the chemokine receptor. GRK5 can also phosphorylate rhodopsin (RHO) in vitro, as well as LRP6, a non G-protein-coupled receptor, during Wnt signaling in vitro.
GRK5 is also known as FP2025, GPRK5.
