Identification of functional divergence sites in dopamine receptors of vertebrates

Xin, Juncai; Fan, Ting; Guo, Pengyi; Wang, Ju

doi:10.1016/j.compbiolchem.2019.107140

Cited by 19 publications

(14 citation statements)

References 53 publications

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“…DR are integral membrane receptors coupled to G proteins ( Beaulieu and Gainetdinov, 2011 ; Thal et al., 2018 ). The dopaminergic system signals through “D1-like” D1 and D5 receptor subtypes and “D2-like”: D2Short (S), D2Long (L), D3 and D4 receptor subtypes ( Xin et al., 2019 ). There is some difference in the affinity of DA for D1-like receptors and D2-like receptors, mostly reported on the basis of receptor-ligand binding studies in recombinant systems ( Supplementary Material: Table 1 ).…”

Section: Section 1: Dopamine Receptorsmentioning

confidence: 99%

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

Martel¹,

McArthur²

2020

Front. Pharmacol.

170

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: Section 1: Dopamine Receptorsmentioning

confidence: 99%

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

Martel¹,

McArthur²

2020

Front. Pharmacol.

170

125

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“…The divergence in the clustering of dopamine receptors may come from their binding site diversity. 60 …”

Section: Resultsmentioning

confidence: 99%

“…However, there are still inconstant examples, for instance, dopamine receptors DRD2 and DRD3 are very similar in sequence but they are not so close in the DISAE embedding tree. The divergence in the clustering of dopamine receptors may come from their binding site diversity …”

Section: Resultsmentioning

confidence: 99%

MSA-Regularized Protein Sequence Transformer toward Predicting Genome-Wide Chemical-Protein Interactions: Application to GPCRome Deorphanization

Lim

Abbu

Qiu

et al. 2021

J. Chem. Inf. Model.

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Small molecules play a critical role in modulating biological systems. Knowledge of chemical–protein interactions helps address fundamental and practical questions in biology and medicine. However, with the rapid emergence of newly sequenced genes, the endogenous or surrogate ligands of a vast number of proteins remain unknown. Homology modeling and machine learning are two major methods for assigning new ligands to a protein but mostly fail when sequence homology between an unannotated protein and those with known functions or structures is low. In this study, we develop a new deep learning framework to predict chemical binding to evolutionary divergent unannotated proteins, whose ligand cannot be reliably predicted by existing methods. By incorporating evolutionary information into self-supervised learning of unlabeled protein sequences, we develop a novel method, distilled sequence alignment embedding (DISAE), for the protein sequence representation. DISAE can utilize all protein sequences and their multiple sequence alignment (MSA) to capture functional relationships between proteins without the knowledge of their structure and function. Followed by the DISAE pretraining, we devise a module-based fine-tuning strategy for the supervised learning of chemical–protein interactions. In the benchmark studies, DISAE significantly improves the generalizability of machine learning models and outperforms the state-of-the-art methods by a large margin. Comprehensive ablation studies suggest that the use of MSA, sequence distillation, and triplet pretraining critically contributes to the success of DISAE. The interpretability analysis of DISAE suggests that it learns biologically meaningful information. We further use DISAE to assign ligands to human orphan G-protein coupled receptors (GPCRs) and to cluster the human GPCRome by integrating their phylogenetic and ligand relationships. The promising results of DISAE open an avenue for exploring the chemical landscape of entire sequenced genomes.

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“…Additionally, although both groups of receptors are coupled to G proteins, D 1 -like receptors are coupled to the Gs type, whereas D 2 -like family receptors are coupled to Gi/Go classes of the G protein. Regarding their structure, D 1 -like receptors show a short third cytoplasmatic loop and a long C-terminal tail, and D 2 -like receptors exhibit a long third cytoplasmic loop and a short C-terminal tail [ 15 , 16 ]. Thus, their ability to bind dopamine as a neurotransmitter is one of their few common features, and it has been proposed that this capacity was acquired by convergent evolution [ 17 , 18 ].…”

Section: Dopaminergic Populations and Receptors In The Lampreymentioning

confidence: 99%

The Dopaminergic Control of Movement-Evolutionary Considerations

Pérez‐Fernández

Barandela

Jiménez-López

2021

IJMS

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Dopamine is likely the most studied modulatory neurotransmitter, in great part due to characteristic motor deficits in Parkinson’s disease that arise after the degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNc). The SNc, together with the ventral tegmental area (VTA), play a key role modulating motor responses through the basal ganglia. In contrast to the large amount of existing literature addressing the mammalian dopaminergic system, comparatively little is known in other vertebrate groups. However, in the last several years, numerous studies have been carried out in basal vertebrates, allowing a better understanding of the evolution of the dopaminergic system, especially the SNc/VTA. We provide an overview of existing research in basal vertebrates, mainly focusing on lampreys, belonging to the oldest group of extant vertebrates. The lamprey dopaminergic system and its role in modulating motor responses have been characterized in significant detail, both anatomically and functionally, providing the basis for understanding the evolution of the SNc/VTA in vertebrates. When considered alongside results from other early vertebrates, data in lampreys show that the key role of the SNc/VTA dopaminergic neurons modulating motor responses through the basal ganglia was already well developed early in vertebrate evolution.

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Identification of functional divergence sites in dopamine receptors of vertebrates

Cited by 19 publications

References 53 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

MSA-Regularized Protein Sequence Transformer toward Predicting Genome-Wide Chemical-Protein Interactions: Application to GPCRome Deorphanization

The Dopaminergic Control of Movement-Evolutionary Considerations

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