scholarly journals GPR171 Activation Modulates Nociceptor Functions, Alleviating Pathologic Pain

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 256
Author(s):  
Pyung Sun Cho ◽  
Han Kyu Lee ◽  
Young In Choi ◽  
Seung In Choi ◽  
Ji Yeon Lim ◽  
...  
Keyword(s):  
Pain Modulation ◽  
G Protein Coupled Receptors ◽  
Peptide Ligand ◽  
Peripheral Pain ◽  
Somatosensory Neurons ◽  
Natural Peptide ◽  
Nociceptive Ion Channels ◽  
Signal Transductions ◽  
G Protein Coupled ◽  
Functional Alteration

Modulation of the function of somatosensory neurons is an important analgesic strategy, requiring the proposal of novel molecular targets. Many G-protein-coupled receptors (GPRs) have been deorphanized, but the receptor locations, outcomes due to their activations, and their signal transductions remain to be elucidated, regarding the somatosensory nociceptor function. Here we report that GPR171, expressed in a nociceptor subpopulation, attenuated pain signals via Gi/o-coupled modulation of the activities of nociceptive ion channels when activated by its newly found ligands. Administration of its natural peptide ligand and a synthetic chemical ligand alleviated nociceptor-mediated acute pain aggravations and also relieved pathologic pain at nanomolar and micromolar ranges. This study suggests that functional alteration of the nociceptor neurons by GPR171 signaling results in pain alleviation and indicates that GPR171 is a promising molecular target for peripheral pain modulation.

NMR studies of CCK-8/CCK1 complex support membrane-associated pathway for ligand-receptor interaction

2002 ◽  
Vol 80 (5) ◽  
pp. 383-387 ◽  
Author(s):  
Craig Giragossian ◽  
Maria Pellegrini ◽  
Dale F Mierke
Keyword(s):  
G Protein ◽  
Structural Features ◽  
G Protein Coupled Receptors ◽  
Peptide Ligands ◽  
Receptor Interaction ◽  
Peptide Ligand ◽  
Receptor Subtype ◽  
Nmr Studies ◽  
Receptor Complexes ◽  
G Protein Coupled

The interaction of peptide ligands with their associated G-protein-coupled receptors has been examined by a number of different experimental approaches over the years. We have been developing an approach utilizing high-resolution NMR to determine the structural features of the peptide ligand, well-designed fragments of the receptor, and the ligand–receptor complexes formed upon titration of the peptide hormone. The results from these investigations provide evidence for a membrane-associated pathway for the initial interaction of peptide ligands with the receptor. Here, our results from the investigation of the interaction of CCK-8 with the CCK1 receptor are described. Our spectroscopic results clearly show that both CCK-8 and the regions of CCK1 with which it interacts are closely associated with the zwitterionic interface of the lipids utilized in our solution spectroscopic studies.Key words: G-protein-coupled receptors, NMR structural characterization, cholecystokinin, CCK-8, cholecystokinin receptor, subtype 1, CCK1, peptide hormones.

scholarly journals Cell-Free Assay of G-Protein-Coupled Receptors Using Fluorescence Polarization

2008 ◽  
Vol 13 (5) ◽  
pp. 424-429 ◽  
Author(s):  
Jessi Wildeson Jones ◽  
Tiffani A. Greene ◽  
Christine A. Grygon ◽  
Benjamin J. Doranz ◽  
Martha P. Brown
Keyword(s):  
G Protein ◽  
Fluorescence Polarization ◽  
G Protein Coupled Receptors ◽  
Peptide Ligand ◽  
Binding Assays ◽  
Free System ◽  
Molecular Binding ◽  
Soluble Cell ◽  
G Protein Coupled ◽  
Peptide Interaction

A recently developed nanotechnology, the Integral Molecular lipoparticle, provides an essentially soluble cell-free system in which G-protein-coupled receptors (GPCRs) in their native conformations are concentrated within virus-like particles. As a result, the lipoparticle provides a means to overcome 2 common obstacles to the development of homogeneous, nonradioactive GPCR ligand-binding assays: membrane protein solubilization and low receptor density. The work reported here describes the first application of this nanotechnology to a fluorescence polarization (FP) molecular binding assay format. The GPCR chosen for these studies was the well-studied chemokine receptor CXCR4 for which a peptide ligand (T-22) has been previously characterized. The EC50 determined for the CXCR4-T-22 peptide interaction via FP with CXCR4 lipoparticles (15 nM) is consistent with the IC50 determined for the unlabeled T-22 peptide via competitive binding (59 nM). ( Journal of Biomolecular Screening 2008:424-429)

scholarly journals β-Barrel scaffolds for the grafting of extracellular loops from G-protein-coupled receptors

2012 ◽  
Vol 393 (11) ◽  
pp. 1341-1355 ◽  
Author(s):  
Reto Walser ◽  
Jörg H. Kleinschmidt ◽  
Arne Skerra ◽  
Oliver Zerbe
Keyword(s):  
G Protein ◽  
Structural Information ◽  
Binding Mode ◽  
G Protein Coupled Receptors ◽  
Peptide Ligand ◽  
Receptor Ligands ◽  
Natural Systems ◽  
Comprehensive Information ◽  
Chimeric Construct ◽  
G Protein Coupled

Abstract Owing to the difficulties in production and purification of G-protein-coupled receptors (GPCRs), relatively little structural information is available about this class of receptors. Here we aim at developing small chimeric proteins, displaying the extracellular ligand-binding motifs of a human GPCR, the Y receptor. This allows the study of ligand-receptor interactions in simplified systems. We present comprehensive information on the use of transmembrane (OmpA) and soluble (Blc) β-barrel scaffolds. Whereas Blc appeared to be not fully compatible with our approach, owing to problems with refolding of the hybrid constructs, loop-grafted versions of OmpA delivered encouraging results. Previously, we described a chimeric construct based on OmpA displaying all three extracellular Y1 receptor loops in different topologies and showing moderate affinity to one of the natural ligands. Now, we present detailed data on the interaction of these constructs with several Y receptor ligands along with data on new constructs. Our findings suggest a common binding mode for all ligands, which is mediated through the C-terminal residues of the peptide ligand, supporting the functional validity of these hybrid receptors. The observed binding affinities, however, are well below those observed for the natural receptors, clearly indicating limitations in mimicking the natural systems.

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