Chemokine Receptor Expression and Regulatory Mechanisms
Thomas R. O’Brien in Chemokine Receptors and AIDS, 2019
Desensitization is defined as diminished responsiveness of a signaling system to subsequent stimuli following initial stimulation (48). The mechanism of G-protein-coupled receptor desensitization has been studied in great detail for the visual and adrenergic systems (48, 49). From these studies, two types of desensitization, termed “homologous” and “heterologous,” have been described. Homologous desensitization occurs in receptors in the agonist-occupied state and involves phosphorylation by G-protein-coupled receptor kinases. Several of the G-protein-coupled receptor kinases were identified in leukocytes (50). Homologously phosphorylated receptors associate with members of the arrestin family of proteins which results in a decreased affinity of the receptor for G-proteins and in receptor internalization.
Dopamine Receptors, Signaling Pathways, and Drugs
Nira Ben-Jonathan in Dopamine, 2020
GPCR desensitization was initially attributed to the phosphorylation of ligand-occupied receptors by second messenger–dependent protein kinases such as protein kinase A (PKA), or protein kinase C (PKC) [39,40]. Following the discovery of the GRKs and β-arrestins, a more comprehensive model of desensitization has emerged [7]. As illustrated in Figure 2.8, this model posits that occupancy of the receptor by an agonist promotes the coupling of the receptor to G proteins and induces the activation of proximal effectors such as GRK. Upon receptor phosphorylation at specific sites on the ICLs and C-terminus by GRKs, the receptor becomes a high-affinity target for β-arrestins. Binding of β-arrestins promotes the receptor uncoupling from the G proteins in spite of continuous occupancy by the agonist. The phosphorylated receptor/β-arrestin complex is then targeted to clathrin-coated pits, followed by endocytosis and internalization. Once internalized, the receptors can either undergo dephosphorylation and recycle back to the plasma membrane, or they can be translocated to the lysosomes for degradation. It has been proposed that the sequence of residues that GRK phosphorylates on the receptor may regulate how β-arrestin functions following receptor binding and may determine whether the receptor is recycled or degraded.
Supersensitivity and Desensitization
Kenneth J. Broadley in Autonomic Pharmacology, 2017
Also present in crude preparations of β-ARK was a factor termed β-arrestin. This is analogous to arrestin, the 48 kDa protein that inactivates rhodopsin kinase in the rhodopsin photoreceptor system. β-ARK is comparable with rhodopsin kinase, the retinal enzyme that phosphorylates and inactivates only the light-bleached form of rhodopsin. Thus, arrestin inhibits transducin, the retinal G protein, from interacting with the phosphorylated rhodopsin. β-Arrestin interacts with the β-ARK phosphorylated receptor leading to enhanced uncoupling from the Gs regulatory protein. Therefore both β-ARK and β-arrestin are required for this agonist-specific phosphorylation and uncoupling process, leading to homologous desensitization. Human β-ARK has now been cloned and sequenced. It also interacts with the βγ-subunits of the G protein by the C-terminal portion of β-ARK. The β-ARK-βγ complex is thereby anchored in the cell membrane and allows for more efficient receptor phosphorylation and desensitization. This would occur when the receptors are activated to release the βτ-subunit and would thus facilitate termination of receptor activation through the phosphorylation process.
Evaluating oliceridine as a treatment option for moderate to severe acute post-operative pain in adults
Published in Expert Opinion on Pharmacotherapy, 2022
Zhaosheng Jin, Mingxi Zhu, Abhishek Gupta, Christopher Page, Tong J Gan, Sergio D Bergese
In addition, mu opioid receptor activation leads to activation of regulatory pathways, this includes the β-arrestin pathway and the Regulators of G protein signaling (RGS) proteins. Arrestin is a class of small regulatory proteins which binds to phosphorylated G protein-coupled receptors, this then leads to the deactivation and internalization of the bound receptor [37,38]. RGS proteins are multi-functional, GTPase-accelerating proteins which promotes the hydrolysis of GTP by the Gα subunit; this converts Gα- GTP to the inactive Gα- GDP which subsequently binds and deactivates the βγ complex [39]. These regulatory processes serve to prevent prolonged opioid receptor activation and are implicated in the development of opioid tolerance [40]. In addition, while the mechanism is not clear, the β-arrestin pathway is also thought to contribute to the ORAEs.
Functional GLP-1R antibodies identified from a synthetic GPCR-focused library demonstrate potent blood glucose control
Published in mAbs, 2021
Qiang Liu, Pankaj Garg, Burcu Hasdemir, Linya Wang, Emily Tuscano, Emily Sever, Erica Keane, Ana G Lujan Hernandez, Tom Z. Yuan, Eric Kwan, Joyce Lai, Greg Szot, Sreenivasan Paruthiyil, Fumiko Axelrod, Aaron K. Sato
When a GPCR is activated by an agonist, β-arrestins are recruited to the GPCR from the cytosol, thereby excluding the receptor from further G protein interactions and leading to signal arrest, hence the name “arrestin”.35 To determine if TB01-3 had any effects on β-arrestin recruitment by activated GLP-1 R, GLP-1 R-over-expressing CHO-K1 cells (DiscoverX) that are specifically designed and validated for assessing GLP-1 R β-arrestin recruitment were used in the following manner. Cells were pre-incubated with a 3-fold titration of TB01-3 from 100 nM down for 1 hr at room temperature (RT) to allow binding to occur and then stimulated with 10 nM GLP-1 7–36. TB01-3 demonstrated inhibition of GLP-1 7–36 peptide-induced beta arrestin recruitment to GLP-1 R in a dose-response curve for β-arrestin recruitment (Figure 8c). This indicated that TB01-3 reduces β-arrestin recruitment to GLP-1 R, which is consistent with the observed reduced receptor activation. Thus, these cell-based assays indicate that TB01-3 is an antagonist to GLP-1 7–36 for GLP-1 R.
β-arrestin 2 quenches TLR signaling to facilitate the immune evasion of EPEC
Published in Gut Microbes, 2020
Zijuan Chen, Ruixue Zhou, Yihua Zhang, Doudou Hao, Yu Wang, Shichao Huang, Ningning Liu, Chunmei Xia, Nissan Yissachar, Feng Huang, Yiwei Chu, Dapeng Yan
β-arrestin 2 is distributed in most mammalian tissues and cells and was originally identified as a negative regulator in the desensitization and internalization of heterotrimeric guanine nucleotide-binding protein-coupled receptor (GPCR). After phosphorylation of GPCRs by GPCR kinases (GRKs), β-arrestins translocate from the cytoplasm to the cell membrane and directly interact with the phosphorylated GPCRs, resulting in the dissociation of receptors from heterotrimeric G proteins, which quenches GPCR signaling.19,20 Besides, β-arrestin 2 acts as a scaffold protein by associating with various signaling molecules to change its binding partners’ distribution and modulate their activity, such as Src family kinases, E3 ligase, and MAP kinases.21,22 For example, when stimulated with Ang II, a β-arrestin 2 activator, JNK3 was exported from the nucleus and co-localized with β-arrestin 2 in the endosome, where ASK1 phosphorylated JNK3 in a β-arrestin 2-dependent manner.23 Furthermore, accumulating studies have indicated that β-arrestin 2 plays an important role in regulating immune signaling. For example, β-arrestin 2 interacts with TRAF6 to negatively regulate TLR signaling in innate immunity,24 inhibits insulin resistance by regulating Src and Akt signaling, and interacts with KIR2DL1 in NK cells to facilitate inhibitory signaling.25 These results suggest that β-arrestin 2 functions in various signaling pathways by interacting with different molecules. However, whether β-arrestin 2 plays roles in host and microbe interaction is unclear.
Related Knowledge Centers
- G Protein
- Photoreceptor Cell
- Protein
- Rhodopsin
- Signal Transduction
- Phosphorylation
- G Protein-Coupled Receptor
- Serine/Threonine-Specific Protein Kinase
- G Protein-Coupled Receptor Kinase
- Arrestin Beta 2