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.

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 Synthesis, Structural and Thermal Studies of 3-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-ethoxy-1H-indole (D2AAK1_3) as Dopamine D2 Receptor Ligand

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2249 ◽  
Author(s):  
Magda Kondej ◽  
Agata Bartyzel ◽  
Monika Pitucha ◽  
Tomasz Wróbel ◽  
Andrea Silva ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Thermal Stability ◽  
Dopamine D2 Receptor ◽  
Thermal Studies ◽  
D2 Receptor ◽  
Thermal Characterization ◽  
X Ray ◽  
Good Thermal Stability ◽  
Dopamine D2

Compound D2AAK1_3 was designed as a modification of the lead structure D2AAK1 (an in vivo active multi-target compound with nanomolar affinity to a number of aminergic GPCRs) and synthesized in the reaction of 5-ethoxyindole and 1-benzyl-4-piperidone. This compound has an affinity to the human dopamine D2 receptor with Ki of 151 nM. The aim of these studies was the structural and thermal characterization of the compound D2AAK1_3. In particular; X-ray studies; molecular docking and molecular dynamics as well as thermal analysis were performed. The studied compound crystallizes in orthorhombic system; in chiral space group P212121. The compound has a non-planar conformation. The studied compound was docked to the novel X-ray structure of the human dopamine D2 receptor in the inactive state (PDB ID: 6CM4) and established the main contact between its protonatable nitrogen atom and Asp (3.32) of the receptor. The obtained binding pose was stable in molecular dynamics simulations. Thermal stability of the compound was investigated using the TG-DSC technique in the air atmosphere, while TG-FTIR analyses in air and nitrogen atmospheres were also performed. The studied compound is characterized by good thermal stability. The main volatile products of combustion are the following gases: CO2; H2O toluene and CO while in the case of pyrolysis process in the FTIR spectra; the characteristic bands of NH3; piperidine and indole are additionally observed.

scholarly journals PCM1 is necessary for focal ciliary integrity and is a candidate for severe schizophrenia

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Tanner O. Monroe ◽  
Melanie E. Garrett ◽  
Maria Kousi ◽  
Ramona M. Rodriguiz ◽  
Sungjin Moon ◽  
...  
Keyword(s):  
Primary Cilium ◽  
Antipsychotic Drugs ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Postnatal Brain ◽  
Physiological Relevance ◽  
Rare Alleles ◽  
Pericentriolar Material ◽  
G Protein Coupled

AbstractThe neuronal primary cilium and centriolar satellites have functions in neurogenesis, but little is known about their roles in the postnatal brain. We show that ablation of pericentriolar material 1 in the mouse leads to progressive ciliary, anatomical, psychomotor, and cognitive abnormalities. RNAseq reveals changes in amine- and G-protein coupled receptor pathways. The physiological relevance of this phenotype is supported by decreased available dopamine D2 receptor (D2R) levels and the failure of antipsychotic drugs to rescue adult behavioral defects. Immunoprecipitations show an association with Pcm1 and D2Rs. Finally, we sequence PCM1 in two human cohorts with severe schizophrenia. Systematic modeling of all discovered rare alleles by zebrafish in vivo complementation reveals an enrichment for pathogenic alleles. Our data emphasize a role for the pericentriolar material in the postnatal brain, with progressive degenerative ciliary and behavioral phenotypes; and they support a contributory role for PCM1 in some individuals diagnosed with schizophrenia.

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.

Dopamine D2 Receptor Blockade and Antimigraine Action of Flunarizine

Cephalalgia ◽  
1994 ◽  
Vol 14 (3) ◽  
pp. 235-240 ◽  
Author(s):  
C Wöber ◽  
T Brücke ◽  
C Wöber-Bingöl ◽  
S Asenbaum ◽  
P Wessely ◽  
...  
Keyword(s):  
Single Photon ◽  
Dopamine D2 Receptor ◽  
Photon Emission ◽  
D2 Receptor ◽  
High Specificity ◽  
D2 Receptors ◽  
Binding Potential ◽  
Receptor Blockade ◽  
Dopamine D2

We studied in vivo the influence of flunarizine on dopamine D2 receptors and investigated whether dopamine D2 receptor blockade is involved in its antimigraine action. Eleven migraine patients, treated with flunarizine, 10 mg per day, underwent single photon emission computer tomography (SPECT) using [123I] labeled iodobenzamide, a ligand with high affinity and high specificity for D2 receptors. There was a reduction of the dopamine D2 receptor binding potential in all patients compared to age-matched controls. The efficacy of flunarizine in migraine prophylaxis failed to correlate with the degree of the dopamine D2 receptor blockade. The antimigraine action of flunarizine may not involve antidopaminergic mechanisms.

Steele-Richardson-Olszewski-Syndrome: Reduction of dopamine D2 receptor binding relates to the severity of midbrain atrophy in vivo:123IBZM SPECT and MRI study

2002 ◽  
Vol 17 (3) ◽  
pp. 557-562 ◽  
Author(s):  
Guy Arnold ◽  
Klaus Tatsch ◽  
Eduardo Kraft ◽  
Wolfgang H. Oertel ◽  
Johannes Schwarz
Keyword(s):  
Receptor Binding ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Dopamine D2 ◽  
Mri Study

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.

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