scholarly journals Distinct antagonist-bound inactive states underlie the divergence in the structures of the dopamine D2 and D3 receptors

2019 ◽  
Author(s):  
J. Robert Lane ◽  
Ara M. Abramyan ◽  
Ravi Kumar Verma ◽  
Herman D. Lim ◽  
Jonathan A. Javitch ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Helical Conformation ◽  
Binding Studies ◽  
D3 Receptors ◽  
Dopamine D2 ◽  
Extracellular Loops ◽  
Rational Drug ◽  
G Protein Coupled ◽  
Receptor Conformation

ABSTRACTUnderstanding how crystal structures reflect the range of possible G protein-coupled receptor (GPCR) states is critical for rational drug discovery (RDD). Combining computational simulations with mutagenesis and binding studies, we find that the structure of the dopamine D2 receptor (D2R)/risperidone complex captures an inactive receptor conformation that accommodates some but not all antagonist scaffolds. Indeed, we find that eticlopride binds D2R in a configuration very similar to that seen in the D3R structure, in a pose that is incompatible with the D2R/risperidone structure. Moreover, our simulations reveal that extracellular loops 1 and 2 (EL1 and EL2) are highly dynamic, with spontaneous transitions of EL2 from the helical conformation in the D2R/risperidone structure to an extended conformation similar to that in the D3R/eticlopride structure. Our results highlight previously unappreciated conformational diversity and dynamics in the inactive state of a GPCR with potential functional implications. These findings are also of paramount importance for RDD as limiting a virtual screen to one state will miss relevant ligands.

scholarly journals Distinct inactive conformations of the dopamine D2 and D3 receptors correspond to different extents of inverse agonism

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
J Robert Lane ◽  
Ara M Abramyan ◽  
Pramisha Adhikari ◽  
Alastair C Keen ◽  
Kuo-Hao Lee ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Helical Conformation ◽  
Extracellular Loop ◽  
D3 Receptors ◽  
Virtual Screen ◽  
Dopamine D2 ◽  
Extracellular Loops ◽  
Inverse Agonism ◽  
Rational Drug ◽  
Loop 2

By analyzing and simulating inactive conformations of the highly homologous dopamine D2 and D3 receptors (D2R and D3R), we find that eticlopride binds D2R in a pose very similar to that in the D3R/eticlopride structure but incompatible with the D2R/risperidone structure. In addition, risperidone occupies a sub-pocket near the Na+ binding site, whereas eticlopride does not. Based on these findings and our experimental results, we propose that the divergent receptor conformations stabilized by Na+-sensitive eticlopride and Na+-insensitive risperidone correspond to different degrees of inverse agonism. Moreover, our simulations reveal that the extracellular loops are highly dynamic, with spontaneous transitions of extracellular loop 2 from the helical conformation in the D2R/risperidone structure to an extended conformation similar to that in the D3R/eticlopride structure. Our results reveal previously unappreciated diversity and dynamics in the inactive conformations of D2R. These findings are critical for rational drug discovery, as limiting a virtual screen to a single conformation will miss relevant ligands.

The Effect of PAOPA, a Novel Allosteric Modulator of Dopamine D2 Receptors, on Select Signaling Proteins Following Sub-Chronic Administration in the Rat

2020 ◽  
Vol 13 ◽  
Author(s):  
Ritesh Daya ◽  
Joella Ho ◽  
Sharon Thomson ◽  
Jayant Bhandari ◽  
Ram K. Mishra
Keyword(s):  
Frontal Cortex ◽  
Mechanism Of Action ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Dorsal Striatum ◽  
D2 Receptors ◽  
Dopamine D2 ◽  
Therapeutic Mechanism ◽  
Clinical Models ◽  
G Protein Coupled

Background: Allosteric modulators of G-protein coupled receptors regulate receptor activity by binding to sites other than the active site and have emerged as a new and highly desirable class of drugs. PAOPA (3(R)-[(2(S)- pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide), a peptidomimetic analog of Prolyl-Leucyl-Glycinamide, is a potent dopamine D2 receptor allosteric modulator. PAOPA has shown therapeutic effects in pre-clinical models of schizophrenia and extrapyramidal dysfunction. Objective: in this study, we sought to examine the biomolecular underpinnings of PAOPA‘s therapeutic outcomes in preclinical models of schizophrenia. Method: Following sub-chronic (daily for 7 days) administration of PAOPA, we assessed levels of dopamine D2 receptors, receptor kinases (GRK2 (G protein-coupled receptor kinase 2) and Arrestin-3), and phosphorylated mitogenactivated protein kinase (MAPKs), namely, extracellular signal-regulated kinases (ERK1/2) in the hippocampus, medial pre-frontal cortex, nucleus accumbens, pre-frontal cortex, and dorsal striatum via protein quantification. Results: Following 7 days of daily PAOPA treatment, we observed decreased GRK2 and increased dopamine D2 receptor expression in the dorsal striatum. These findings potentially underscore PAOPA’s therapeutic mechanism of action for the positive-like symptoms of schizophrenia in pre-clinical animal models. Additionally, we observed a decline in GRK2 in the hippocampus and an increase in phosphorylated ERK1 in the pre-frontal cortex, suggestive of a role for PAOPA in treating cognitive and/or affective dysfunction in pre-clinical models. Conclusion: While further studies are required to elucidate PAOPA’s mechanism of action, this study builds on prior investigations and develops an early framework to describe the therapeutic mechanism of action of PAOPA.

scholarly journals Preferential Coupling of Dopamine D2S and D2L Receptor Isoforms with Gi1 and Gi2 Proteins—In Silico Study

2020 ◽  
Vol 21 (2) ◽  
pp. 436 ◽  
Author(s):  
Justyna Żuk ◽  
Damian Bartuzi ◽  
Dariusz Matosiuk ◽  
Agnieszka A. Kaczor
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Antipsychotic Agents ◽  
Intracellular Loop ◽  
Dopamine D2 ◽  
Receptor Isoforms ◽  
In Silico Study ◽  
Third Intracellular Loop ◽  
G Protein Coupled ◽  
Insight Into

The dopamine D2 receptor belongs to rhodopsin-like G protein-coupled receptors (GPCRs) and it is an important molecular target for the treatment of many disorders, including schizophrenia and Parkinson’s disease. Here, computational methods were used to construct the full models of the dopamine D2 receptor short (D2S) and long (D2L) isoforms (differing with 29 amino acids insertion in the third intracellular loop, ICL3) and to study their coupling with Gi1 and Gi2 proteins. It was found that the D2L isoform preferentially couples with the Gi2 protein and D2S isoform with the Gi1 protein, which is in accordance with experimental data. Our findings give mechanistic insight into the interplay between isoforms of dopamine D2 receptors and Gi proteins subtypes, which is important to understand signaling by these receptors and their mediation by pharmaceuticals, in particular psychotic and antipsychotic agents.

scholarly journals The Class-A GPCR Dopamine D2 Receptor Forms Transient Dimers Stabilized by Agonists: Detection by Single-Molecule Tracking

2017 ◽  
Vol 76 (1-2) ◽  
pp. 29-37 ◽  
Author(s):  
Rinshi S. Kasai ◽  
Shuichi V. Ito ◽  
Ryo M. Awane ◽  
Takahiro K. Fujiwara ◽  
Akihiro Kusumi
Keyword(s):  
Single Molecule ◽  
Resting State ◽  
Dopamine D2 Receptor ◽  
Critical Role ◽  
D2 Receptor ◽  
G Protein Coupled Receptors ◽  
Single Molecule Tracking ◽  
Class A ◽  
Dopamine D2 ◽  
G Protein Coupled

Abstract Whether class-A G-protein coupled receptors (GPCRs) exist and work as monomers or dimers has drawn extensive attention. A class-A GPCR dopamine D2 receptor (D2R) is involved in many physiological and pathological processes and diseases, indicating its critical role in proper functioning of neuronal circuits. In particular, D2R homodimers might play key roles in schizophrenia development and amphetamine-induced psychosis. Here, using single-molecule imaging, we directly tracked single D2R molecules in the plasma membrane at a physiological temperature of 37 °C, and unequivocally determined that D2R forms transient dimers with a lifetime of 68 ms in its resting state. Agonist addition prolonged the dimer lifetime by a factor of ~1.5, suggesting the possibility that transient dimers might be involved in signaling.

scholarly journals Evidence for Two Modes of Binding of the Negative Allosteric Modulator SB269,652 to the Dopamine D2 Receptor

Biomedicines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 22
Author(s):  
Richard Ågren ◽  
Kristoffer Sahlholm
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Binding Pocket ◽  
Binding Mode ◽  
Allosteric Modulator ◽  
Drug Candidates ◽  
Dopamine D2 ◽  
Inward Rectifier Potassium Channels ◽  
Negative Allosteric Modulator ◽  
G Protein Coupled

SB269,652 has been described as the first negative allosteric modulator (NAM) of the dopamine D2 receptor (D2R), however, the binding mode and allosteric mechanism of action of this ligand remain incompletely understood. SB269,652 comprises an orthosteric, primary pharmacophore and a secondary (or allosteric) pharmacophore joined by a hydrophilic cyclohexyl linker and is known to form corresponding interactions with the orthosteric binding site (OBS) and the secondary binding pocket (SBP) in the D2R. Here, we observed a surprisingly low potency of SB269,652 to negatively modulate the D2R-mediated activation of G protein-coupled inward-rectifier potassium channels (GIRK) and decided to perform a more detailed investigation of the interaction between dopamine and SB269,652. The results indicated that the SB269,652 inhibitory potency is increased 6.6-fold upon ligand pre-incubation, compared to the simultaneous co-application with dopamine. Mutagenesis experiments implicated both S193 in the OBS and E95 in the SBP in the effect of pre-application. The present findings extend previous knowledge about how SB269,652 competes with dopamine at the D2R and may be useful for the development of novel D2R ligands, such as antipsychotic drug candidates.

scholarly journals Impact of membrane lipid polyunsaturation on dopamine D2 receptor ligand binding and signaling

2022 ◽  
Author(s):  
Marie-Lise Jobin ◽  
Veronique De Smedt-Peyrusse ◽  
Fabien Ducrocq ◽  
Asma Oummadi ◽  
Rim Baccouch ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Dopamine D2 Receptor ◽  
Second Messengers ◽  
D2 Receptor ◽  
Membrane Lipid ◽  
Allosteric Modulators ◽  
Dopamine D2 ◽  
Dynamics Simulations ◽  
G Protein Coupled

The heterogenous and dynamic constitution of the membrane fine-tunes signal transduction. In particular, the polyunsaturated fatty acid (PUFA) tails of phospholipids influence the biophysical properties of the membrane, production of second messengers, or membrane partitioning. Few evidence mostly originating from studies of rhodopsin suggest that PUFAs directly modulate the conformational dynamic of transmembrane proteins. However, whether such properties translate to other G protein-coupled receptors remains unclear. We focused on the dopamine D2 receptor (D2R), a main target of antipsychotics. Membrane enrichment in n-3, but not n-6, PUFAs potentiates ligand binding. Molecular dynamics simulations show that the D2R preferentially interacts with n-3 over n-6 PUFAs. Furthermore, even though this mildly affects signalling in heterologous systems, in vivo n-3 PUFA deficiency blunts the effects of D2R ligands. These results suggest that n-3 PUFAs act as allosteric modulators of the D2R and provide a putative mechanism for their potentiating effect on antipsychotic efficacy.

scholarly journals G protein-coupled kinase 2 attenuates dopamine D2 receptor-mediated activation of zif268 promoter in COS-7 cells

2000 ◽  
Vol 82 ◽  
pp. 136
Author(s):  
Ken Iwata ◽  
Norihiro Yoshida ◽  
Tatsuhiko Ebihara ◽  
Toshiyuki Hirabayashi ◽  
David Saffen ◽  
...  
Keyword(s):  
G Protein ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Dopamine D2 ◽  
G Protein Coupled
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