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Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, 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.
Disease Prediction and Drug Development
Published in Arvind Kumar Bansal, Javed Iqbal Khan, S. Kaisar Alam, Introduction to Computational Health Informatics, 2019
Arvind Kumar Bansal, Javed Iqbal Khan, S. Kaisar Alam
Most proteins are multifunctional and interact with more than one type of proteins. Some examples are kinases and arrestin. Kinase is a large class of enzymes responsible for phosphorylation – transfer of a phosphate group from a high-energy ATP molecule or another substrate. Arrestin is a small class of regulatory proteins that bind to G-protein-coupled receptors (GPCR). GPCR is a large family of trans-membrane receptors outside a cell to sense biomolecules.
Chemokine Receptor Expression and Regulatory Mechanisms
Published in Thomas R. O’Brien, Chemokine Receptors and AIDS, 2019
Ricardo M. Richardson, Ralph Snyderman, Bodduluri Haribabu
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.
Opioid MOP receptor agonists in late-stage development for the treatment of postoperative pain
Published in Expert Opinion on Pharmacotherapy, 2022
Qiu Qiu, Joshua CJ Chew, Michael G Irwin
Tolerance is the reduced effect of a drug after repeated administration, or the requirement for dose escalation to achieve the same effect. Tolerance is well described with the chronic use of opioids but can also occur in the acute setting. The occurrence of acute tolerance is clinically, a function of dose, time, and fractional receptor occupancy [36]. After activation, the MOP receptor is phosphorylated by kinases including GPCR kinase. The phosphorylated receptor subsequently binds to β-arrestin. β-arrestin mediates the formation of endocytic complexes and receptor internalization [15]. Reduction in available receptors in the cell membrane results in pharmacological tolerance. A reduction in the recruitment of β-arrestin may lead to decreased tolerance and this is a therapeutic target for new drugs [37]. Moreover, the NOP receptor may also play a role in tolerance, with studies reporting attenuated tolerance with NOP receptor agonism and antagonism [38, 39].
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.