Molecular Interrogation of Dopaminergic System Responsiveness: From Neurons to Receptors

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Molecular and Cellular Neuroscience".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 13019

Special Issue Editor


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Guest Editor
Neurosciences Program, Ottawa Hospital Research Institute & Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada
Interests: Dopamine; G Protein-Coupled Receptors; Structure-Activity Relationships; Signaling; Phosphorylation; Densitization; Endocytosis; Interactome; Proteomics; Motor Behavior; Parkinson’s Disease; Dyskinesia; Stroke

Special Issue Information

Dear Colleagues,

The history of 3,4-dihydroxyphenylethylamine, or dopamine, research started 110 years ago with its synthesis by chemists George Barger and Arthur James Ewins at the Wellcome labs in London, England. For a long time, dopamine was not considered physiologically important until the discovery of its naturally occuring metabolic precursor, levodopa (L-DOPA), and DOPA decarboxylase, the enzyme that converts levodopa into dopamine. Nonetheless, dopamine was still believed to be only an essential precursor in the biosynthesis of the star neurotransmitters, noradrenaline and adrenaline. Dopamine was maintained in this role of “best supporting actor” for noradrenaline and adrenaline up until ground-breaking work done notably by Oleh Hornykiewicz, Arvid Carlsson and Paul Greengard labs, from the 1950s to the end of 1970s, granted true neurotransmitter status to dopamine with a patent of nobility. In this day and age, dopamine is fully recognized as one of the most important brain neurotransmitters, which modulates a wide array of central and peripheral physiological actions. These actions converge onto neural substrates implicated in motor activity, learning, memory, mood, reward, and nociception. Two major subgroups of cell-surface transmembrane G protein-coupled receptors known as D1-class (D1 and D5) and D2-class (D2, D3, and D4) subtypes coordinate the pre- and postsynaptic actions of dopamine. Most importantly, an imbalance in dopamine activity is associated with the phenotypic expression of several neurological and psychiatric disorders such as Parkinson’s disease, schizophrenia, and drug addiction. While over the last 25 years, studies have begun to uncover the underlying structural and molecular underpinnings that regulate dopamine neurons and its receptors, more work is needed to fully appreciate the mechanistic rules governing dopamine activity at the neuronal and receptor levels.

In this Special Issue entitled “Molecular Interrogation of Dopaminergic System Responsiveness: From Neurons to Receptors”, we welcome the submission of original research using state-of-the-art techniques as well as review articles on the topic of molecular regulation of dopamine activity mediated through either neurons or various dopaminergic receptor subtypes. It is hoped that this Special Issue will inspire new ideas and approaches for the design of novel therapeutics to treat conditions with compromised dopaminergic neurotransmission.

Dr. Mario Tiberi
Guest Editor

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Keywords

  • dopamine
  • G protein-coupled receptors
  • phosphorylation
  • desensitization
  • endocytosis and sorting
  • dimerization
  • biased signaling
  • neuronal activity
  • tyrosine hydroxylase
  • proteomics
  • transcriptomics
  • neurogenesis
  • axonal regulation
  • dendritic activity
  • pre-clinical dopamine-based disease models

Published Papers (4 papers)

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Research

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12 pages, 3521 KiB  
Article
Sex Differences in Dopamine Receptor Signaling in Fmr1 Knockout Mice: A Pilot Study
by Anlong Jiang, Le Wang, Justin Y. D. Lu, Amy Freeman, Charlie Campbell, Ping Su, Albert H. C. Wong and Fang Liu
Brain Sci. 2021, 11(11), 1398; https://doi.org/10.3390/brainsci11111398 - 24 Oct 2021
Cited by 4 | Viewed by 2003
Abstract
Fragile X syndrome (FXS) is an X-chromosome-linked dominant genetic disorder that causes a variable degree of cognitive dysfunction and developmental disability. Current treatment is symptomatic and no existing medications target the specific cause of FXS. As with other X-linked disorders, FXS manifests differently [...] Read more.
Fragile X syndrome (FXS) is an X-chromosome-linked dominant genetic disorder that causes a variable degree of cognitive dysfunction and developmental disability. Current treatment is symptomatic and no existing medications target the specific cause of FXS. As with other X-linked disorders, FXS manifests differently in males and females, including abnormalities in the dopamine system that are also seen in Fmr1-knockout (KO) mice. We investigated sex differences in dopamine signaling in Fmr1-KO mice in response to L-stepholidine, a dopamine D1 receptor agonist and D2 receptor antagonist. We found significant sex differences in basal levels of phosphorylated protein kinase A (p-PKA) and glycogen synthase kinase (GSK)-3β in wild type mice that were absent in Fmr1-KO mice. In wild-type mice, L-stepholidine increased p-PKA in males but not female mice, decreased p-GSK-3 in female mice and increased p-GSK-3 in male mice. Conversely, in Fmr1-KO mice, L-stepholidine increased p-PKA and p-GSK-3β in females, and decreased p-PKA and p-GSK-3β in males. Full article
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23 pages, 4240 KiB  
Article
Ouabain-Induced Gene Expression Changes in Human iPSC-Derived Neuron Culture Expressing Dopamine and cAMP-Regulated Phosphoprotein 32 and GABA Receptors
by Alexander V. Lopachev, Maria A. Lagarkova, Olga S. Lebedeva, Margarita A. Ezhova, Rogneda B. Kazanskaya, Yulia A. Timoshina, Anastasiya V. Khutorova, Evgeny E. Akkuratov, Tatiana N. Fedorova and Raul R. Gainetdinov
Brain Sci. 2021, 11(2), 203; https://doi.org/10.3390/brainsci11020203 - 07 Feb 2021
Cited by 2 | Viewed by 2854
Abstract
Cardiotonic steroids (CTS) are specific inhibitors and endogenous ligands of a key enzyme in the CNS—the Na+, K+-ATPase, which maintains and creates an ion gradient on the plasma membrane of neurons. CTS cause the activation of various signaling cascades [...] Read more.
Cardiotonic steroids (CTS) are specific inhibitors and endogenous ligands of a key enzyme in the CNS—the Na+, K+-ATPase, which maintains and creates an ion gradient on the plasma membrane of neurons. CTS cause the activation of various signaling cascades and changes in gene expression in neurons and other cell types. It is known that intracerebroventricular injection of cardiotonic steroid ouabain causes mania-like behavior in rodents, in part due to activation of dopamine-related signaling cascades in the dopamine and cAMP-regulated phosphoprotein 32 (DARPP-32) expressing medium spiny neurons in the striatum. Dopaminergic projections in the striatum innervate these GABAergic medium spiny neurons. The objective of this study was to assess changes in the expression of all genes in human iPSC-derived expressing DARPP-32 and GABA receptors neurons under the influence of ouabain. We noted a large number of statistically significant upregulated and downregulated genes after a 16-h incubation with non-toxic concentration (30 nM) of ouabain. These changes in the transcriptional activity were accomplished with activation of MAP-kinase ERK1/2 and transcriptional factor cAMP response element-binding protein (CREB). Thus, it can be concluded that 30 nM ouabain incubated for 16 h with human iPSC-derived expressing DARPP-32 and GABA receptors neurons activates genes associated with neuronal maturation and synapse formation, by increasing the expression of genes associated with translation, vesicular transport, and increased electron transport chain function. At the same time, the expression of genes associated with proliferation, migration, and early development of neurons decreases. These data indicate that non-toxic concentrations of ouabain may induce neuronal maturation, neurite growth, and increased synaptogenesis in dopamine-receptive GABAergic neurons, suggesting formation of plasticity and the establishment of new neuronal junctions. Full article
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14 pages, 2175 KiB  
Article
Mitigating Effects of Liriope platyphylla on Nicotine-Induced Behavioral Sensitization and Quality Control of Compounds
by Dahye Yoon, In Soo Ryu, Woo Cheol Shin, Minhan Ka, Hyoung-Geun Kim, Eun Young Jang, Oc-Hee Kim, Young-Seob Lee, Joung-Wook Seo and Dae Young Lee
Brain Sci. 2020, 10(9), 654; https://doi.org/10.3390/brainsci10090654 - 21 Sep 2020
Cited by 2 | Viewed by 2279
Abstract
In this study we investigated the mitigating effects of Liriope platyphylla Wang et Tang extract on behavioral sensitization and the quantification of its major compounds. The extract of L. platyphylla reduces the expression of tyrosine hydroxylase (TH) protein, which is increased by nicotine, [...] Read more.
In this study we investigated the mitigating effects of Liriope platyphylla Wang et Tang extract on behavioral sensitization and the quantification of its major compounds. The extract of L. platyphylla reduces the expression of tyrosine hydroxylase (TH) protein, which is increased by nicotine, back to normal levels, and increases the expression of dopamine transporter (DAT) protein, which is reduced by nicotine, back to normal levels in PC12 cells. In this study, rats received nicotine (0.4 mg/kg, subcutaneously) only for seven days and then received extract of L. platyphylla (200 or 400 mg/kg, oral) 1 h prior to nicotine administration for an additional seven days. The extract of L. platyphylla reduced locomotor activity compared to the nicotine control group in rats. The extract of L. platyphylla significantly attenuated the repeated nicotine-induced DAT protein expression in the nucleus accumbens (NAc), but there was no effect on increased TH protein expression in the dorsal striatum. These findings suggest that L. platyphylla extract has a mitigating effect on nicotine-induced behavioral sensitization by modulating DAT protein expression in the NAc. For quality control of L. plathyphylla, spicatoside A and D, which are saponin compounds, were quantified in the L. platyphylla extract. The amounts of spicatoside A and D in L. platyphylla extract obtained from ultra-high-performance liquid chromatography with tandem mass spectrometry were 0.148 and 0.272 mg/g, respectively. The identification of these compounds in L. platyphylla, which can be used for quality control, provides important information for the development of drugs to treat nicotine dependence. Full article
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Review

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16 pages, 362 KiB  
Review
Sex Differences in Dopamine Receptors and Relevance to Neuropsychiatric Disorders
by Olivia O. F. Williams, Madeleine Coppolino, Susan R. George and Melissa L. Perreault
Brain Sci. 2021, 11(9), 1199; https://doi.org/10.3390/brainsci11091199 - 11 Sep 2021
Cited by 34 | Viewed by 5252
Abstract
Dopamine is an important neurotransmitter that plays a key role in neuropsychiatric illness. Sex differences in dopaminergic signaling have been acknowledged for decades and have been linked to sex-specific heterogeneity in both dopamine-related behaviours as well as in various neuropsychiatric disorders. However, the [...] Read more.
Dopamine is an important neurotransmitter that plays a key role in neuropsychiatric illness. Sex differences in dopaminergic signaling have been acknowledged for decades and have been linked to sex-specific heterogeneity in both dopamine-related behaviours as well as in various neuropsychiatric disorders. However, the overall number of studies that have evaluated sex differences in dopamine signaling, both in health and in these disorders, is low. This review will bring together what is known regarding sex differences in innate dopamine receptor expression and function, as well as highlight the known sex-specific roles of dopamine in addiction, depression, anxiety, schizophrenia, and attention deficit hyperactivity disorder. Due to differences in prognosis, diagnosis, and symptomatology between male and female subjects in disorders that involve dopamine signaling, or in responses that utilize pharmacological interventions that target dopamine receptors, understanding the fundamental sex differences in dopamine receptors is of vital importance for the personalization of therapeutic treatment strategies. Full article
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