Serine/threonine kinase that phosphorylates preferentially the activated forms of a variety of G-protein-coupled receptors (GPCRs). Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their down-regulation. Phosphorylates a variety of GPCRs, including adrenergic receptors, muscarinic acetylcholine receptors (more specifically Gi-coupled M2/M4 subtypes), dopamine receptors and opioid receptors. In addition to GPCRs, also phosphorylates various substrates: Hsc70-interacting protein/ST13, TP53/p53, HDAC5, and arrestin-1/ARRB1. 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) leading to nuclear export of HDAC5 and allowing MEF2-mediated transcription. Phosphorylation of TP53/p53, a crucial tumor suppressor, inhibits TP53/p53-mediated apoptosis. Phosphorylation of ST13 regulates internalization of the chemokine receptor (By similarity). Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor, LRP6 during Wnt signaling (in vitro) (By similarity). [G-protein-coupled receptor] + ATP = [G-protein-coupled receptor]-phosphate + ADP + H(+) Inhibited by calmodulin with an IC(50) of 50 nM. Calmodulin inhibits GRK5 association with receptor and phospholipid (By similarity). Interacts with ST13 (via the C-terminus 303-319 AA) (By similarity). Interacts with TP53/p53 (By similarity). Interacts with HTR4 (via C-terminus 330-346 AA); this interaction is promoted by 5-HT (serotonin) (By similarity). Interacts with HDAC5 (By similarity). Interacts with GIT1 (PubMed:9826657). Predominantly localized at the plasma membrane, targeted to the cell surface through the interaction with phospholipids. Nucleus localization is regulated in a GPCR and Ca(2+)/calmodulin-dependent fashion (By similarity). Not expressed ubiquitously in brain but is mainly localize in limbic brain regions with a very prominent expression in the lateral septal area. By cocaine in the lateral septum. Up-regulated in the failing heart. Autophosphorylated. Autophosphorylation may play a critical role in the regulation of GRK5 kinase activity. Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. GPRK subfamily.