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Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, Dopamine, 2020
Based on structural, pharmacological, and biochemical properties, the five known DARs were subdivided into D1-like (D1R and D5R), which increase cAMP, and D2-like (D2R, D3R and D4R), which inhibit cAMP. This early classification, which was solely based on changes in cAMP levels, is now considered oversimplified and not sufficiently encompassing. Although the same DAR classification is still in use today, the signaling cascades which are activated by the DARs are much more variable and complex. The newer concepts are based on advanced knowledge of the noncanonical signaling pathways induced by the DARs, the combinatorial signaling outcome that results from receptor oligomerization, and the roles that are played by proximal effectors such as G protein-independent β-arrestins, and G protein-coupled receptor kinases (GRKs).
The N-Formylpeptide Chemotactic Receptor
Published in Richard Horuk, Chemoattractant Ligands and Their Receptors, 2020
Studies with the prototype G protein-coupled receptors rhodopsin and the β2 adrenergic receptor have indicated the importance of receptor phosphorylation in the desensitization phenomenon.119 Two type of desensitizing phosphorylation events have been described: homologous desensitization which involves phosphorylation of ligand-occupied receptors by G protein-coupled receptor kinases (GRK), and heterologous desensitization which involves phosphorylation of receptors unoccupied by ligand by protein kinase A. A family of at least 7 human genes encoding known or putative G protein-coupled receptor kinases has been identified by cDNA cloning.127,128 The best characterized members of this family, the β adrenergic receptor kinases (βARK) 1 and 2, and rhodopsin kinase, have been shown to function in a stimulus-dependent fashion for several different receptor substrates. βARK1 and βARK2 (GRK2 and 3), and the gene for a recently identified putative GRK designated GPRK6 are expressed in neutrophils, and all other human tissues examined. Genes for additional putative GRKs, designated GPRK5 and GPRK7, were identified by homology PCR in human neutrophils.128 GRKs translocate from the cytosol to their substrates on the plasma membrane in response to specific types of agonist stimulation. Given the large number of known G protein-coupled receptors, it will be interesting to determine whether they are regulated by a similarly large family of receptor kinases.
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.
Exosomes derived from GIT1-overexpressing bone marrow mesenchymal stem cells promote traumatic spinal cord injury recovery in a rat model
Published in International Journal of Neuroscience, 2021
Yongjun Luo, Tao Xu, Wei Liu, Yuluo Rong, Jiaxing Wang, Jin Fan, Guoyong Yin, Weihua Cai
G protein-coupled receptor kinase 2 interacting protein 1 (GIT1), a multifunction and multidomain scaffold protein, was first identified for its binding to GRK2 and its effects on adrenergic receptor endocytosis [22]. It works as a regulation of cytoskeletal dynamics and an integrator of signaling pathways during cell spreading, adhesion and migration, receptor internalization, synapse formation and cytoskeletal organization [23–25]. Several studies have showed that GIT1 could regulate cardiac mitochondrial biogenesis, cell survival and is essential in stimulating intestinal epithelial restitution [26,27]. It was also demonstrated that GIT1 deficiency mice might have a chondrocyte differentiation and fracture-healing delay resulting from decreased revascularization and increased apoptosis [21,28,29].
Small molecule and peptide-based CXCR4 modulators as therapeutic agents. A patent review for the period from 2010 to 2018
Published in Expert Opinion on Therapeutic Patents, 2020
Yesim A Tahirovic, Sameshnee Pelly, Edgars Jecs, Eric J Miller, Savita K Sharma, Dennis C Liotta, Lawrence J Wilson
CXCL12 binding to CXCR4 stimulates Gαi/o-mediated inhibition of adenylyl cyclase and concomitant reduction in cAMP levels, as well as Gα15-mediated release of intracellular calcium stores. It also indirectly regulates the PI-3K/Akt, MAPK and JAK/STAT pathways [14]. Accordingly, measurements of intracellular cAMP levels and calcium flux are the two most common methods employed for assessment of CXCR4 activation, as well as the potencies of ligands that modulate CXCR4 activity [33,34]. These are routine assays in the field of GPCR research and many are available for purchase. There are also cases where special adaptations have been invented either using novel reagents, techniques or cell types. Some of the cell types used here include CCRF-CEM, HEK293 and HeLa cells. Alternatively, Gαi/o proteins also stimulate phosphorylation of extracellular signal-related kinase (ERK) commonly measured using ELISA or western blot to quantitate CXCR4 activation and modulation. As is characteristic of most GPCRs, agonist-mediated CXCR4 activation results in G protein-coupled receptor kinase (GRK)-catalyzed phosphorylation of intracellular GPCR residues, thereby recruiting β-arrestin proteins to the plasma membrane to facilitate receptor internalization. Cellular dielectric spectroscopy is an alternative method capable of capturing more nuanced information by producing ‘a series of receptor-specific, frequency-dependent impedance patterns’ that can be differentially modulated by ligands with different on-target activities [35].
Current strategies toward safer mu opioid receptor drugs for pain management
Published in Expert Opinion on Therapeutic Targets, 2019
Aliza T. Ehrlich, Brigitte L. Kieffer, Emmanuel Darcq
Ligand-receptor interactions have long-been viewed as a two-step process, first the ligand binds to a receptor inducing a conformational change that second, initiates downstream signaling pathways [12]. Over the years pharmacological studies have further demonstrated that ligands may have functional selectivity or ‘biased agonism’ at different receptor-effector (i.e. G proteins, G protein-coupled receptor kinases (GRKs), arrestins) complexes to activate distinct pathways, which together give rise to wanted and unwanted drug effects [13]. In fact, the signaling response depends on the active ligand-receptor-effector complex that is formed and determines the downstream biological consequences [14,15]. Designing biased ligands to induce a receptor conformation that elicits a distinct and preferred effect on cellular signaling is a current drug discovery strategy that could yield drugs with high potency, low toxicity and few adverse effects [16].