G protein-coupled receptor kinases: More than just kinases and not only for GPCRs

Abstract

G protein-coupled receptor (GPCR) kinases (GRKs) are best known for their role in homologous desensitization of GPCRs. GRKs phosphorylate activated receptors and promote high affinity binding of arrestins, which precludes G protein coupling. GRKs have a multidomain structure, with the kinase domain inserted into a loop of a regulator of G protein signaling homology domain. Unlike many other kinases, GRKs do not need to be phosphorylated in their activation loop to achieve an activated state. Instead, they are directly activated by docking with active GPCRs. In this manner they are able to selectively phosphorylate Ser/Thr residues on only the activated form of the receptor, unlike related kinases such as protein kinase A. GRKs also phosphorylate a variety of non-GPCR substrates and regulate several signaling pathways via direct interactions with other proteins in a phosphorylation-independent manner. Multiple GRK subtypes are present in virtually every animal cell, with the highest expression levels found in neurons, with their extensive and complex signal regulation. Insufficient or excessive GRK activity was implicated in a variety of human disorders, ranging from heart failure to depression to Parkinson’s disease. As key regulators of GPCR-dependent and -independent signaling pathways, GRKs are emerging drug targets and promising molecular tools for therapy. Targeted modulation of expression and/or of activity of several GRK isoforms for therapeutic purposes was recently validated in cardiac disorders and Parkinson’s disease.

Neutrophil Elastase Activates Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) to Cause Inflammation and Pain

“…Conversely, we observed that elastase-activated PAR 2 was unable to recruit GRK2, interact with ␤-arrestins, or undergo endocytosis. The lack of GRK2 recruitment by elastase-activated PAR 2 is consistent with the lack of ␤-arrestin recruitment, which is known to rely on GRKmediated phosphorylation of agonist-occupied receptors (57). Our findings support a previous report that elastase-activated PAR 2 is unable to recruit ␤-arrestins (32).…”

Peptide substrates for G protein‐coupled receptor kinase 2

“…GRKs control the signaling and activation of G protein-coupled receptors (GPCRs) through the phosphorylation of GPCRs [1,2]. Deregulation of GRK-mediated GPCR phosphorylation has been associated with a number of cardiovascular diseases (e.g., hypertension and heart failure) [1][2][3][4], brain diseases (e.g., Alzheimer disease) [1,5], and with certain types of cancers [6,7]. GRK2 (formerly known as b-adrenergic receptor kinase 1) was found to be overexpressed in various brain and cardiovascular diseases, and is therefore considered to be a potential therapeutic target for these diseases [2][3][4][5].…”

“…In this study, consensus substrate motifs for GRK2 were identified from the sequences of GRK2 protein substrates, and 17 candidate peptides were synthesized to identify peptide substrates with high affinity for GRK2. GRK2 appears to require an acidic amino acid at the À2, À3, or À4 positions and its consensus phosphorylation site motifs were identified as (D/ E)X [1][2][3] …”

Raf Kinase Inhibitor Protein (RKIP) Dimer Formation Controls Its Target Switch from Raf1 to G Protein-coupled Receptor Kinase (GRK) 2

“…In mammalian cells, GRK2 is a major feedback inhibitor of GPCRs and has been shown to be implicated among others in psychiatric disorders, immune diseases, and cardiovascular diseases (25)(26)(27). Binding of RKIP to GRK2 inhibits GRK2 kinase activity, which leads to enhanced GPCR signaling.…”