Comprehensive Technology Information
G protein-coupled receptor kinases (GRKs) are a group of kinases related to the rapid desensitization of G protein-coupled receptors (GPCRs). Many GPCRs such as opioid receptors, thromboxane receptors, 52 serotonin receptors, and adrenergic receptors are prone to rapid attenuation of transduction signals when the agonist is continuously stimulated. This regulatory mechanism is mainly related to GRKs. The GRKs family consists of 7 family members with structurally homologous sequences. Each GRKs contains a common functional structure, including a central catalytic region, a substrate recognition and amino-terminal region containing regulators of Gprotein signaling (RGS) -like structure, and an action on the arboxy-terminal region of the membrane.
Figure 1. Protein structure of G protein-coupled receptor kinase (GRKs).
Classifications
According to the similarity of sequence and function, it can be divided into 3 subfamilies.
The first subfamily includes GRK1 and GRK7. GRK1 is a rhodopsin kinase, which is expressed only in retinal photoreceptor cells, and its substrate is retinal opsin.
The second subfamily of GRK2 and GRK3 is also known as β2 adrenergic receptor kinase 1 (β2ARK1) and β2 adrenergic receptor kinase 2 (β2ARK2).
The third subfamily includes GRK4, GRK5 and GRK6.
GRK4 is only expressed at high levels in the testis, suggesting that the enzyme has substrate specificity.
GRKs and GPCRs desensitization
The degree of receptor desensitization can be the complete termination of the signal, such as the visual and olfactory systems; it can also be a decrease in the effectiveness of agonists, such as β2AR. The degree of receptor desensitization is affected by many factors including the structure of the receptor and the cellular environment. The main feature is that the receptor is uncoupled from the heterotrimeric G protein. Termination of GPCRs signaling can also occur at the G protein level. When the receptor is not activated, GRK1 ~ 3 exists in the cytoplasm; after the receptor is activated, GRK123 transfers to the cell membrane and binds to the target receptor.
Structure
X-ray crystal structures of multiple GRKs (GRK1, GRK2, GRK4, GRK5, and GRK6) alone or in combination with a ligand have been obtained. In general, GRKs have sequence homology and domain organization, in which the central protein kinase catalytic domain is preceded by a domain homologous to the active domain of a G protein modulator, a signaling protein, and an RGS protein (RGS Homology-RH-domain) is followed by a variable carboxy-terminal tail regulatory region. In folded proteins, the kinase domain forms a typical bilobate kinase structure with a central ATP-binding active site. The RH domain consists of an amino-terminal sequence plus an alpha-helix region formed by a short sequence after the kinase domain. This sequence provides two additional helices and makes extensive contact with one side of the kinase domain. Modeling and mutagenesis show that RH domain senses GPCR activation to open kinase active site
G protein-coupled receptor kinase 2
G protein coupled receptor kinase 2 (GRK2) is an enzyme encoded by the ADRBK1 gene in humans. GRK2 was originally called β-adrenergic receptor kinase (βARK or βARK1), and is a member of the G protein-coupled receptor kinase subfamily of Ser/Thr protein kinases, which is most similar to GRK3 (βARK2 is the most similar).
Figure 2. Structure of the GRK2 protein.
G protein-coupled receptor kinase 6
This gene encodes a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinase family, which is most similar to GRK4 and GRK5. This protein phosphorylates an activated form of the G protein-coupled receptor to regulate the signaling.
Figure 3. Structure of the GRK6 protein.
G protein-coupled receptor kinase 7
GRK7 is a member of the G protein coupled receptor kinase family and is officially named G protein coupled receptor kinase 7. GRK7 is mainly found in mammalian retinal cone cells and phosphorylates photoactivated photoproteinases, a member of the family. G protein-coupled receptors recognize light of various wavelengths (red, green, blue).
Functions
GRK1 is involved in the phosphorylation and inactivation of rhodopsin, and is also related to inhibin 1 (also known as S antigen). Defects in GRK1 can cause small-mouth still night blindness. GRK7, like pyramidin rhodopsin, also known as inhibin 4 or X-arrestin, also regulates phosphorylation and inactivation of cone protein in color vision. GRK2 was first identified as an enzyme that phosphorylates β-2 adrenergic receptors, and was originally called β adrenergic receptor kinase (βARK or ββARK1). GRK2 is overexpressed in heart failure, and GRK2 inhibition can be used to treat heart failure in the future. The polymorphism of the GRK4 gene has been linked to hereditary hypertension and acquired hypertension, and works in part through renal dopamine receptors. Among mature sperm cells, GRK4 is the highest GRK expressed at the mRNA level, but mice lacking GRK4 can still reproduce, so its role in these cells is still unknown. In humans, the GRK5 sequence polymorphism of residue 41 (leucine rather than glutamine), the most common residue in individuals of African ancestry, results in GRK5-mediated airway β2 adrenergic receptors (a Drug targets). In zebrafish and humans, the loss of GRK5 function is related to heterologous heart defects. Heterogeneity is a series of developmental defects caused by incorrect left-right laterality during organ formation. In mice, GRK6 regulation of D2 dopamine receptors in the striatum of the brain changes sensitivity to psychostimulants that work through dopamine, and GRK6 is associated with Parkinson's disease and anti-Parkinson's therapy with drug L Dyskinesia is related to side effects.
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