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

Żuk, Justyna; Bartuzi, Damian; Matosiuk, Dariusz; Kaczor, Agnieszka A.

doi:10.3390/ijms21020436

Cited by 14 publications

(13 citation statements)

References 74 publications

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“…D2-like receptors (D2/D3) are the main targets of antipsychotics . The D2 receptor is present in two isoforms D2S and D2L which differ because of a 29 AA insertion in the third intracellular loop on D2L (Zuk et al, 2020). Both receptors can inhibit intracellular cAMP via Gi.…”

Section: D2/d3 Receptorsmentioning

confidence: 99%

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

Martel¹,

McArthur²

2020

Front. Pharmacol.

177

125

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Dopamine receptors are widely distributed within the brain where they play critical modulator roles on motor functions, motivation and drive, as well as cognition. The identification of five genes coding for different dopamine receptor subtypes, pharmacologically grouped as D1- (D1 and D5) or D2-like (D2S, D2L, D3, and D4) has allowed the demonstration of differential receptor function in specific neurocircuits. Recent observation on dopamine receptor signaling point at dopamine—glutamate-NMDA neurobiology as the most relevant in schizophrenia and for the development of new therapies. Progress in the chemistry of D1- and D2-like receptor ligands (agonists, antagonists, and partial agonists) has provided more selective compounds possibly able to target the dopamine receptors homo and heterodimers and address different schizophrenia symptoms. Moreover, an extensive evaluation of the functional effect of these agents on dopamine receptor coupling and intracellular signaling highlights important differences that could also result in highly differentiated clinical pharmacology. The review summarizes the recent advances in the field, addressing the relevance of emerging new targets in schizophrenia in particular in relation to the dopamine – glutamate NMDA systems interactions.

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Section: D2/d3 Receptorsmentioning

confidence: 99%

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

Martel¹,

McArthur²

2020

Front. Pharmacol.

177

125

View full text Add to dashboard Cite

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“…The receptor was simulated in complex with G protein, and composition of the lipid bilayer reflected properties of lipid rafts [ 31 ]. This methodology proved to be successful in previous studies on other MOR modulators [ 22 , 23 , 24 ] and other subtle allosteric effects in other GPCRs [ 32 ]. Notably, investigation of compounds 1 and 2 yielded results compatible with in vitro and in vivo observations, as well as with studies of other modulators of opioid receptors.…”

Section: Discussionmentioning

confidence: 91%

Novel Positive Allosteric Modulators of µ Opioid Receptor—Insight from In Silico and In Vivo Studies

Bartuzi¹,

Kędzierska²,

Kaczor

et al. 2020

IJMS

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Opioids are the drugs of choice in severe pain management. Unfortunately, their use involves serious, potentially lethal side effects. Therefore, efforts in opioid drug design turn toward safer and more effective mechanisms, including allosteric modulation. In this study, molecular dynamics simulations in silico and ‘writhing’ tests in vivo were used to characterize potential allosteric mechanism of two previously reported compounds. The results suggest that investigated compounds bind to μ opioid receptor in an allosteric site, augmenting action of morphine at subeffective doses, and exerting antinociceptive effect alone at higher doses. Detailed analysis of in silico calculations suggests that first of the compounds behaves more like allosteric agonist, while the second compound acts mainly as a positive allosteric modulator.

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“…All these processes together were manifested as a decrease in the FRET efficiency, as compared to the basal signal (FRET for D 2 R-Gαi pair). It is noteworthy that in several earlier reports, Gαi 2 was also indicated as selective toward D 2 R, causing maximal inhibition of adenylate cyclase [26,76,77]. However, the experimental data imply that the coupling selectivity of Gαi is regulated by the agonist-activated conformation of D 2 R. For example, stimulation of D 2 R with R(+)-3-PPP hydrochloride caused preferential coupling to Gαi 3 rather than Gαi 1 or Gαi 2 [25].…”

Section: Table 1 Lateral Diffusion Characteristics Of Gα Subunits In mentioning

confidence: 90%

The Gαi protein subclass selectivity to the dopamine D2 receptor is also decided by their location at the cell membrane

et al. 2020

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Background G protein-coupled receptor (GPCR) signaling via heterotrimeric G proteins plays an important role in the cellular regulation of responses to external stimuli. Despite intensive structural research, the mechanism underlying the receptor–G protein coupling of closely related subtypes of Gαi remains unclear. In addition to the structural changes of interacting proteins, the interactions between lipids and proteins seem to be crucial in GPCR-dependent cell signaling due to their functional organization in specific membrane domains. In previous works, we found that Gαs and Gαi3 subunits prefer distinct types of membrane-anchor lipid domains that also modulate the G protein trimer localization. In the present study, we investigated the functional selectivity of dopamine D2 long receptor isoform (D2R) toward the Gαi1, Gαi2, and Gαi3 subunits, and analyzed whether the organization of Gαi heterotrimers at the plasma membrane affects the signal transduction. Methods We characterized the lateral diffusion and the receptor–G protein spatial distribution in living cells using two assays: fluorescence recovery after photobleaching microscopy and fluorescence resonance energy transfer detected by fluorescence-lifetime imaging microscopy. Depending on distribution of data differences between Gα subunits were investigated using parametric approach–unpaired T-test or nonparametric–Mann–Whitney U test. Results Despite the similarities between the examined subunits, the experiments conducted in the study revealed a significantly faster lateral diffusion of the Gαi2 subunit and the singular distribution of the Gαi1 subunit in the plasma membrane. The cell membrane partitioning of distinct Gαi heterotrimers with dopamine receptor correlated very well with the efficiency of D2R-mediated inhibition the formation of cAMP. Conclusions This study showed that even closely related subunits of Gαi differ in their membrane-trafficking properties that impact on their signaling. The interactions between lipids and proteins seem to be crucial in GPCR-dependent cell signaling due to their functional organization in specific membrane domains, and should therefore be taken into account as one of the selectivity determinants of G protein coupling.

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

Cited by 14 publications

References 74 publications

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

Novel Positive Allosteric Modulators of µ Opioid Receptor—Insight from In Silico and In Vivo Studies

The Gαi protein subclass selectivity to the dopamine D2 receptor is also decided by their location at the cell membrane

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