Dataset Information

Voltage-Dependent Dopamine Potency at D1-Like Dopamine Receptors.

ABSTRACT: In recent years, transmembrane voltage has been found to modify agonist potencies at several G protein-coupled receptors (GPCRs). Whereas the voltage sensitivities of the G?i/o-coupled dopamine D2-like receptors (D2R, D3R, D4R) have previously been investigated, the putative impact of transmembrane voltage on agonist potency at the mainly G?s/olf-coupled dopamine D1-like receptors (D1R, D5R) has hitherto not been reported. Here, we assayed the potency of dopamine in activating G protein-coupled inward rectifier potassium (GIRK) channels co-expressed with D1R and D5R in Xenopus oocytes, at -80 mV and at 0 mV. Furthermore, GIRK response deactivation rates upon dopamine washout were measured to estimate dopamine dissociation rate (koff) constants. Depolarization from -80 to 0 mV was found to reduce dopamine potency by about 7-fold at both D1R and D5R. This potency reduction was accompanied by an increase in estimated dopamine koffs at both receptors. While the GIRK response elicited via D1R was insensitive to pertussis toxin (PTX), the response evoked via D5R was reduced by 64% (-80 mV) and 71% (0 mV) in the presence of PTX. Injection of oocytes with G?s antisense oligonucleotide inhibited the D1R-mediated response by 62% (-80 mV) and 76% (0 mV) and abolished the D5R response when combined with PTX. Our results suggest that depolarization decreases dopamine affinity at D1R and D5R. The voltage-dependent affinities of dopamine at D1R and D5R may be relevant to the functions of these receptors in learning and memory.

SUBMITTER: Agren R

PROVIDER: S-EPMC7577048 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Voltage-Dependent Dopamine Potency at D1-Like Dopamine Receptors.

Ågren Richard R Sahlholm Kristoffer K

Frontiers in pharmacology 20201007

In recent years, transmembrane voltage has been found to modify agonist potencies at several G protein-coupled receptors (GPCRs). Whereas the voltage sensitivities of the Gαi/o-coupled dopamine D2-like receptors (D2R, D3R, D4R) have previously been investigated, the putative impact of transmembrane voltage on agonist potency at the mainly Gαs/olf-coupled dopamine D1-like receptors (D1R, D5R) has hi ...[more]

PMID: 33117177

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Project description:Dopamine receptors are integral membrane proteins whose endogenous ligand is dopamine. They play a fundamental role in the central nervous system and dysfunction of dopaminergic neurotransmission is responsible for the generation of a variety of neuropsychiatric disorders. From an evolutionary standpoint, phylogenetic relationships among the DRD1 class of dopamine receptors are still a matter of debate as in the literature different tree topologies have been proposed. In contrast, phylogenetic relationships among the DRD 2 group of receptors are well understood. Understanding the time of origin of the different dopamine receptors is also an issue that needs further study, especially for the genes that have restricted phyletic distributions (e.g., DRD2l and DRD4rs). Thus, the goal of this study was to investigate the evolution of dopamine receptors, with emphasis on shedding light on the phylogenetic relationships among the D1 class of dopamine receptors and the time of origin of the DRD2l and DRD4rs gene lineages. Our results recovered the monophyly of the two groups of dopamine receptors. Within the DRD1 group the monophyly of each paralog was recovered with strong support, and phylogenetic relationships among them were well resolved. Within the DRD1 class of dopamine receptors we recovered the sister group relationship between the DRD1C and DRD1E, and this clade was recovered sister to a cyclostome sequence. The DRD1 clade was recovered sister to the aforementioned clade, and the group containing DRD5 receptors was sister to all other DRD1 paralogs. In agreement with the literature, among the DRD2 class of receptors, DRD2 was recovered sister to DRD3, whereas DRD4 was sister to the DRD2/DRD3 clade. According to our phylogenetic tree, the DRD2l and DRD4rs gene lineages would have originated in the ancestor of gnathostomes between 615 and 473 mya. Conservation of sequences required for dopaminergic neurotransmission and small changes in regulatory regions suggest a functional refinement of the dopaminergic pathways along evolution.

Dataset Information

Voltage-Dependent Dopamine Potency at D1-Like Dopamine Receptors.

Publications

Voltage-Dependent Dopamine Potency at D<sub>1</sub>-Like Dopamine Receptors.

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