G protein-coupled receptors (GPCRs) mediate signal transduction via G protein or β-arrestin. Several biased ligands and receptors that preferentially signal through either G protein- or β-arrestin-mediated pathways have been identified. These discoveries have redefined the classical GPCR signaling paradigm. Distinct ligand-receptor binding sites might be one of the main reasons for biased signal transduction. It is posited that multiple active conformations of receptors lead to distinct kinase phosphorylation patterns on C terminus of receptors. Phosphorylation patterns decide which signal pathway will be transduced. The biased signal pathway transduction has been found in more than 40 GPCRs till now. A few of them have been found involved in fine-regulation of physiological processes. However, most others still need further investigation. The biased ligands may be developed as tools for understanding the basic physiology of GPCR, and, potentially and most importantly, as fine-tuned therapeutics that maximize beneficial effects and minimize adverse or unwanted effects. These studies will provide new insights into new drug discovery.
Ligands ; Phosphorylation ; Receptors, G-Protein-Coupled ; Signal Transduction

Touch ; Signal Transduction ; Receptors, G-Protein-Coupled ; Touch Perception

G protein-coupled receptors(GPCRs)represent the largest class of cell surface receptors,mediating wide range of cellular and physiological processes through their transducers,G proteins and the-arrestins participate in almost all pathological processes. Recent technological advances are revolutionizing the utility of cryo-electron microscopy(cryo-EM),leading to a tremendous progress in the structural studies of biological macromolecules and cryo-EM has played a leading role in the structural biology of GPCR signaling complex. New discoveries of high-resolution threedimensional structures of GPCR signaling complexes based on cryo-EM have emerged vigorously,which depict the common structural characteristics of intermolecular interaction between GPCR and G protein complex-the conformational changes of the transmembrane helix 6 of receptors,and also demonstrate the structural basis of G protein subtype selectivity. Single-particle cryo-EM becomes an efficient tool for identifying the molecular mechanism of receptor-ligand interaction,providing important information for understanding GPCR signaling and the structure-based drug design.
Cryoelectron Microscopy ; Protein Binding ; Protein Structure, Tertiary ; Receptors, G-Protein-Coupled ; chemistry

The molecular vibration-activity relationship in the receptor-ligand interaction of adenosine receptors was investigated by structure similarity, molecular vibration, and hierarchical clustering in a dataset of 46 ligands of adenosine receptors. The resulting dendrogram was compared with those of another kind of fingerprint or descriptor. The dendrogram result produced by corralled intensity of molecular vibrational frequency outperformed four other analyses in the current study of adenosine receptor agonism and antagonism. The tree that was produced by clustering analysis of molecular vibration patterns showed its potential for the functional classification of adenosine receptor ligands.
Adenosine* ; Classification ; Dataset ; Dermatoglyphics ; Felodipine* ; Ligands ; Receptors, G-Protein-Coupled ; Receptors, Purinergic P1* ; Subject Headings ; Vibration

Animals ; Oocytes ; metabolism ; physiology ; Receptors, G-Protein-Coupled ; physiology ; Receptors, Purinergic P2X ; physiology ; Xenopus laevis

OBJECTIVETo analyze the correlation between pituitary stalk interruption syndrome (PSIS) and prokineticin receptor 2 (PROKR2) and prokineticin 2 (RROK2) mutations.

METHODSPROKR2 and RROK2 genotypes were identified by multiplex polymerase chain reaction analysis with exon-flanking primers and by automated sequencing techniques with peripheral blood DNA samples from 59 patients with PSIS.

RESULTSOf these 59 PSIS patients, 6 showed intragenic deletions at the PROKR2 locus. Of them, 5 patients exhibited intragenic subsititution of exon 2 (c.991G>A), and the remaining one patient exhibited intragenic subsititution of exon 2 (c.1057C>T). No PROK2 mutation was found in these PSIS patients.

CONCLUSIONPROKR2 may be the susceptibility gene of PSIS.

In this study, bioinformatics methods such as molecular docking and network pharmacology were adopted to establish Xiaoxuming Decoction (XXMD) "compound-vasodilatory and vasoconstrictory related G protein-coupled receptors (GPCR) targets" network, then the vascular function regulatory effective components and the potential targets of XXMD were analyzed. Based on the XXMD herb sources, the chemical structures of the compounds were retrieved from the national scientific data sharing platform for population and health pharmaceutical information center, TCMSP database and the latest research literatures. The chemical molecular library was established after class prediction and screening for medicinal and metabolic properties. Then, five kinds of vasodilatory and vasoconstrictory related GPCR crystal structure including 5-HT receptors (5-HT1AR, 5-HT1BR), AT1R, β2-AR, hUTR and ETB were retrieved from RCSB Protein Data Bank database or constructed by homology modeling of Discovery Studio 4.1 built-in modeling tools. After virtual screening by Libdock molecular docking, the highest rated 50 compounds of each target were collected and analyzed. The collected data were further used to construct and analyze the network by Cytoscape 3.4.0. The results showed that most of the chemical composition effects were associated with different vasodilatory and vasoconstrictory related GPCR targets, while a few effective components could be applied to multiple GPCR targets at the same time, therefore forming synergies and vasorelaxant effects of XXMD.
Databases, Protein ; Drugs, Chinese Herbal ; Models, Chemical ; Molecular Docking Simulation ; Receptors, G-Protein-Coupled ; metabolism ; Vasodilation

This study was aimed to observe the distribution of Mas-related G protein-coupled receptor A (MrgA) in cerebrospinal fluid (CSF)-contacting nucleus of normal rats and its expression in neuropathic pain, and to provide morphological evidence for CSF-contacting nucleus to participate in neuropathic pain. The model of neuropathic pain with chronic constriction injury (CCI) of the sciatic nerve was made in Sprague-Dawley rats. The thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) were measured. The expressions of MrgA in the CSF-contacting nucleus were examined by double labeling with immunofluorescent staining. The results showed that on the 5th, 7th, 10th and 14th days, the values of MWT and TWL in CCI group were all lower than those in sham group (P < 0.05). MrgA was found to be distributed in CSF-contacting nucleus of normal rats; and the expression was markedly up-regulated in rats at the peak of neuropathic pain. Our data suggest that CSF-contacting nucleus may participate in neuropathic pain through the MrgA-mediated signaling pathway.
Animals ; Neuralgia ; Rats ; Rats, Sprague-Dawley ; Receptors, G-Protein-Coupled/metabolism* ; Staphylococcal Protein A/metabolism* ; Up-Regulation

G-protein-coupled receptors (GPCR) are the largest superfamily of receptors responsible for signaling between cells and tissues, and because they play important physiological roles in homeostasis, they are major drug targets. New technologies have been developed for the identification of new ligands, new GPCR functions, and for drug discovery purposes. In particular, intercellular lipid mediators, such as, lysophosphatidic acid and sphingosine 1-phosphate have attracted much attention for drug discovery and this has resulted in the development of fingolimod (FTY-720) and AM095. The discovery of new intercellular lipid mediators and their GPCRs are discussed from the perspective of drug development. Lipid GPCRs for lysophospholipids, including lysophosphatidylserine, lysophosphatidylinositol, lysophosphatidylcholine, free fatty acids, fatty acid derivatives, and other lipid mediators are reviewed.
Drug Discovery* ; Fatty Acids, Nonesterified ; Homeostasis ; Ligands ; Lysophosphatidylcholines ; Lysophospholipids ; Receptors, G-Protein-Coupled ; Sphingosine ; Fingolimod Hydrochloride

G-protein-coupled receptor 17 (GPR17), an originally orphan receptor, was identified as a new uracil nucleotides/cysteinyl leukotriene receptor. However, whether GPR17 is really classified as a leukotriene receptor is a matter deserving further investigation. GPR17 is involved in many physiological and pathological processes including brain injury, spinal cord injury, and oligodendrocyte differentiation. GPR17 may become a new therapeutic target in these diseases. In this article, the research progress on the pharmacology and pathophysiological roles of GPR17 is reviewed.
Central Nervous System ; injuries ; physiopathology ; Humans ; Neurogenesis ; physiology ; Receptors, G-Protein-Coupled ; metabolism ; physiology