scholarly journals A Novel Dopamine Receptor Signaling Unit in Brain: Heterooligomers of D1 And D2 Dopamine Receptors

2007 ◽  
Vol 7 ◽  
pp. 58-63 ◽  
Author(s):  
Susan R. George ◽  
Brian F. O'Dowd
Keyword(s):  
Dopamine Receptor ◽  
Calcium Release ◽  
D2 Receptor ◽  
Binding Pocket ◽  
Calcium Signal ◽  
Molecular Entity ◽  
D2 Dopamine Receptors ◽  
Receptor Field ◽  
D1 And D2 Receptors ◽  
Definition Of

The ability of G protein coupled receptors to heterooligomerize and create novel signaling complexes has demonstrated the tremendous potential of these receptors to access diverse signaling cascades, as well as to modulate the nature of the transduced signal. In the dopamine receptor field, the existence of a D1-like receptor in brain that activated phospatidylinositol turnover has been shown, but definition of the molecular entity remained elusive. We discovered that the D1 and D2 receptors form a heterooligomer, which on activation of both receptors, coupled to Gq to activate phospholipase C and generate intracellular calcium release. The activation of Gq by the D1-D2 heterooligomer has been shown to occur in cells expressing both receptors, as well as in striatum, distinct from Gs/olf or Gi/o activation by the D1 and D2 receptor homooligomers, respectively. The activation of the D1-D2 receptor heterooligomer in brain led to a calcium signal–mediated increase in phosphorylation of calmodulin kinase lla. The calcium signal rapidly desensitized and the receptors cointernalized after occupancy of either the D1 or D2 binding pocket. Thus, the D1-D2 heterooligomer directly links the action of dopamine to rapid calcium signaling and likely has important effects on dopamine-mediated synaptic plasticity and its functional correlates in brain.

scholarly journals Retrograde labeling illuminates distinct topographical organization of D1 and D2 receptor-positive neurons in the prefrontal cortex of mice

2020 ◽  
Author(s):  
Sara M. Green ◽  
Sanya Nathani ◽  
Joseph Zimmerman ◽  
David Fireman ◽  
Nikhil M. Urs
Keyword(s):  
Prefrontal Cortex ◽  
Dopamine Receptor ◽  
Pyramidal Neurons ◽  
D2 Receptor ◽  
Dorsal Striatum ◽  
Behavioral Flexibility ◽  
Substantia Nigra Pars Compacta ◽  
Projection Neurons ◽  
D1 And D2 Receptors ◽  
Topographical Organization

ABSTRACTThe cortex plays an important role in regulating motivation and cognition, and does so by regulating multiple subcortical brain circuits. Glutamatergic pyramidal neurons in the prefrontal cortex (PFC) are topographically organized in different subregions such as the prelimbic, infralimbic and orbitofrontal, and project to topographically-organized subcortical target regions. Dopamine D1 and D2 receptors are expressed on glutamatergic pyramidal neurons in the PFC. However, it is unclear whether D1 and D2 receptor-expressing pyramidal neurons in the PFC are also topographically organized. We used a retrograde adeno-associated virus (AAVRG)-based approach to illuminate the topographical organization of D1 and D2 receptor-expressing neurons, projecting to distinct striatal and midbrain subregions. Our experiments reveal that AAVRG injection in the nucleus accumbens (NAcc) or dorsal striatum (dSTR) of D1Cre mice labeled distinct neuronal subpopulations in medial orbitofrontal or prelimbic PFC, respectively. However, AAVRG injection in NAcc or dSTR of D2Cre mice labeled medial orbitofrontal, but not medial prelimbic PFC, respectively. Additionally, D2R+ but not D1R+ PFC neurons were labeled upon injection of AAVRG in substantia nigra pars compacta (SNpc). Thus, our data are the first to highlight a unique dopamine receptor-specific topographical pattern in the PFC, which could have profound implications for corticostriatal signaling in the basal ganglia.SIGNIFICANCE STATEMENTCorticostriatal connections play an important role in regulating goal-directed and habitual behavior, and neuromodulators such as cortical dopamine play an important role in behavioral flexibility. Dopamine receptor expressing D1R+ and D2R+ projection neurons in the cortex mediate the effects of cortical dopamine, but whether these neurons are anatomically organized in a manner that would explain how these neurons mediate these complex effects, is not clear. Our results show a distinct topographical organization of D1R+ and D2R+ PFC pyramidal neurons that project to distinct striatal and midbrain subregions. These results suggest that effects of cortical dopamine are mediated by anatomically localized distinct receptor- and target-defined subcircuits.

scholarly journals Discrete and Continuous Cell Identities of the Adult Murine Striatum

2019 ◽  
Author(s):  
Geoffrey Stanley ◽  
Ozgun Gokce ◽  
Robert C. Malenka ◽  
Thomas C. Südhof ◽  
Stephen R. Quake
Keyword(s):  
Dopamine Receptor ◽  
D2 Receptor ◽  
Spatial Relationship ◽  
Cell Types ◽  
Projection Neurons ◽  
Anatomical Location ◽  
D2 Dopamine Receptors ◽  
Spatial Gradients ◽  
Dopamine Receptor 1 ◽  
Combinatorial Mechanism

AbstractThe striatum is a large brain region containing two major cell types: D1 (dopamine receptor 1) and D2 (dopamine receptor 2) expressing spiny projection neurons (SPNs). We generated a cell type atlas of the adult murine striatum using single-cell RNA-seq of SPNs combined with quantitative RNAin situhybridization (ISH). We developed a novel computational pipeline that distinguishes discrete versus continuous cell identities in scRNA-seq data, and used it to show that SPNs in the striatum can be classified into four discrete types that reside in discrete anatomical clusters or are spatially intermingled. Within each discrete type, we find multiple independent axes of continuous cell identity that map to spatial gradients and whose genes are conserved between discrete types. These gradients correlate well to previously-mapped gradients of connectivity. Using these insights, we discovered multiple novel spatially localized region of the striatum, one of which contains patch-D2 SPNs that expressTac1, Htr7, andTh. Intriguingly, we found one subtype that strongly co-expresses both D1 and D2 dopamine receptors, and uniquely expresses a rare D2 receptor splice variant. These results collectively suggest an organizational principal of neuron identity in which major neuron types can be separated into discrete classes with little overlap and no implied spatial relationship. However these discrete classes are then continuously subdivided by multiple spatial gradients of expression defining anatomical location via a combinatorial mechanism. Finally, they suggest that neuronal circuitry has a substructure at far higher resolution than is typically interrogated which is defined by the precise identity and location of a neuron.

scholarly journals Effect of Zishenpingchan Granule on Neurobehavioral Manifestations and the Activity and Gene Expression of Striatal Dopamine D1 and D2 Receptors of Rats with Levodopa-Induced Dyskinesias

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Qing Ye ◽  
Xiao-Lei Yuan ◽  
Jie Zhou ◽  
Can-xing Yuan ◽  
Xu-ming Yang
Keyword(s):  
Gene Expression ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
D2 Receptors ◽  
Striatal Dopamine ◽  
Control Group ◽  
Indirect Pathway ◽  
Dopamine D2 ◽  
D1 And D2 Receptors ◽  
Neurobehavioral Manifestations

This study was performed to observe the effects of Zishenpingchan granule on neurobehavioral manifestations and the activity and gene expression of striatal dopamine D1 and D2 receptors of rats with levodopa-induced dyskinesias (LID). We established normal control group, LID model group, and TCM intervention group. Each group received treatment for 4 weeks. Artificial neural network (ANN) was applied to excavate the main factor influencing variation in neurobehavioral manifestations of rats with LID. The results showed that overactivation in direct pathway mediated by dopamine D1 receptor and overinhibition in indirect pathway mediated by dopamine D2 receptor may be the main mechanism of LID. TCM increased the efficacy time of LD to ameliorate LID symptoms effectively mainly by upregulating dopamine D2 receptor gene expression.

scholarly journals The Carboxy-Terminal Tail of Human Cytomegalovirus (HCMV) US28 Regulates both Chemokine-Independent and Chemokine-Dependent Signaling in HCMV-Infected Cells

2009 ◽  
Vol 83 (19) ◽  
pp. 10016-10027 ◽  
Author(s):  
Melissa P. Stropes ◽  
Olivia D. Schneider ◽  
William A. Zagorski ◽  
Jeanette L. C. Miller ◽  
William E. Miller
Keyword(s):  
Human Cytomegalovirus ◽  
Calcium Release ◽  
Hcmv Infection ◽  
Calcium Signal ◽  
Terminal Domain ◽  
Carboxy Terminal Domain ◽  
Domain Truncation ◽  
Infected Cells ◽  
Heterologous Expression Systems ◽  
Carboxy Terminal

ABSTRACT The human cytomegalovirus (HCMV)-encoded G-protein-coupled receptor (GPCR) US28 is a potent activator of a number of signaling pathways in HCMV-infected cells. The intracellular carboxy-terminal domain of US28 contains residues critical for the regulation of US28 signaling in heterologous expression systems; however, the role that this domain plays during HCMV infection remains unknown. For this study, we constructed an HCMV recombinant virus encoding a carboxy-terminal domain truncation mutant of US28, FLAG-US28/1-314, to investigate the role that this domain plays in US28 signaling. We demonstrate that US28/1-314 exhibits a more potent phospholipase C-β (PLC-β) signal than does wild-type US28, indicating that the carboxy-terminal domain plays an important role in regulating agonist-independent signaling in infected cells. Moreover, HMCV-infected cells expressing the US28/1-314 mutant exhibit a prolonged calcium signal in response to CCL5, indicating that the US28 carboxy-terminal domain also regulates agonist-dependent signaling. Finally, while the chemokine CX3CL1 behaves as an inverse agonist or inhibitor of constitutive US28 signaling to PLC-β, we demonstrate that CX3CL1 functions as an agonist with regard to US28-stimulated calcium release. This study is the first to demonstrate that the carboxy terminus of US28 controls US28 signaling in the context of HCMV infection and indicates that chemokines such as CX3CL1 can decrease constitutive US28 signals and yet simultaneously promote nonconstitutive US28 signals.

scholarly journals A Complete Assessment of Dopamine Receptor-Ligand Interactions through Computational Methods

2019 ◽  
Author(s):  
Beatriz Bueschbell ◽  
Carlos A.V. Barreto ◽  
Antonio J. Preto ◽  
Anke C. Schiedel ◽  
Irina S. Moreira
Keyword(s):  
Dopamine Receptor ◽  
Electrostatic Interactions ◽  
Specific Binding ◽  
Binding Pocket ◽  
Binding Mode ◽  
Receptor Subtypes ◽  
Receptor Ligand ◽  
Pi Stacking ◽  
Ligand Interactions ◽  
New Treatments

Background: Selectively targeting dopamine receptors has been a persistent challenge in the last years for the development of new treatments to combat the large variety of diseases evolving these receptors. Although, several drugs have been successfully brought to market, the subtype-specific binding mode on a molecular basis has not been fully elucidated. Methods: Homology modeling and molecular dynamics were applied to construct robust conformational models of all dopamine receptor subtypes (D1-like and D2-like receptors). Fifteen structurally diverse ligands were docked to these models. Contacts at the binding pocket were fully described in order to reveal new structural findings responsible for DR sub-type specificity. Results: We showed that the number of conformations for a receptor:ligand complex was associated to unspecific interactions > 2.5 Å and hydrophobic contacts, while the decoys binding energy was influenced by specific electrostatic interactions. Known residues such as 3.32Asp, the serine microdomain and the aromatic microdomain were found interacting in a variety of modes (HB, SB, π-stacking). Purposed TM2-TM3-TM7 microdomain was found to form a hydrophobic network involving Orthosteric Binding Pocket (OBP) and Secondary Binding Pocket (SBP). T-stacking interactions revealed as especially relevant for some large ligands such as apomorphine, risperidone or aripiprazole. Conclusions: This in silico approach was successful in showing known receptor-ligand interactions as well as in determining unique combinations of interactions, key for the design of more specific ligands.

scholarly journals The Place of the Dopaminergic Agonists in the Treatment of Parkinson’s Disease: the View from the Trenches

1992 ◽  
Vol 19 (S1) ◽  
pp. 156-159
Author(s):  
David B. King
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopamine Receptor ◽  
Current Practice ◽  
Dopamine Receptor Agonist ◽  
Early Disease ◽  
D1 And D2 Receptors ◽  
Ultimate Failure ◽  
Eventual Loss ◽  
Dying Cells

ABSTRACT:The use of the dopamine receptor agonists in Parkinson’s disease has a compelling logic. These agents are supposed to act independently of the dying cells of the substantia nigra directly on the cells of the striatum. Early clinical trials in advanced disease were only mildly impressive. Later they were found to be beneficial in early disease but their effectiveness waned. Their ultimate failure may reflect the fact that the majority of current agents do not stimulate D1 and D2 receptors in a physiologic ratio. The drugs may act presynaptically and with the eventual loss of the anatomic relationships between nigra and striatum the drugs fail. There is, however, a rationale to their current use. When used along with L-Dopa in early disease the development of late-stage fluctuations are reduced with the same anti-parkinsonian benefits. Merging this concept with the demonstrated effect of selegiline in slowing the course of the disease, the current practice of triple therapy with selegiline, L-Dopa and a dopamine receptor agonist emerges.

scholarly journals Differential allosteric modulation within dopamine D2R - neurotensin NTS1R and D2R - serotonin 5-HT2AR receptor complexes gives bias to intracellular calcium signalling

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Michael Plach ◽  
Thorsten Schäfer ◽  
Dasiel Oscar Borroto-Escuela ◽  
Dorothée Weikert ◽  
Peter Gmeiner ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Calcium Signalling ◽  
Proximity Ligation Assay ◽  
Receptor Interaction ◽  
Calcium Signal ◽  
Ht22 Cells ◽  
Receptor Complexes ◽  
Novel Target ◽  
External Stimuli

Abstract Proceeding investigations of G protein-coupled receptor (GPCR) heterocomplexes have demonstrated that the dopamine D2 receptor (D2R), one of the hub receptors in the physiology of schizophrenia, interacts with both the neurotensin NTS1 (NTS1R) and the serotonin 5-HT2A receptor (5-HT2AR) in cell lines and rodent brain tissue. In situ proximity ligation assay and BRET-based saturation experiments confirmed interacting receptor assemblies in HEK293T and neuronal HT22 cells. The NTS1R agonist NT(8-13) reduces the Gαq-mediated calcium signal in the NTS1R-D2R complex compared to the NTS1R monomer which could be reversed by D2R antagonists. The bivalent ligand CS148 (NTS1R-agonistic, D2R-antagonistic) increased the calcium response addressing the dimer, consistent with the effect of the monovalent ligands suggesting an allosteric D2R-mediated modulation. In contrast, the 5-HT2AR-D2R heteromer did not show a calcium-altering receptor-receptor interaction. Despite their common coupling-preference for Gαq, 5-HT2AR and NTS1R supposedly interact with D2R each in a unique mode. This remarkably diverse ligand-mediated signalling in two different D2R heteroreceptor complexes illustrates the complexity of receptor-receptor interactions and their potential of modifying cell responses to external stimuli. Therefore, GPCR heteromers may provide a very promising novel target for the therapy of neuropsychiatric disorders.

scholarly journals Parametric Images of the Extrastriatal D2 Receptor Density Obtained Using a High-Affinity Ligand (FLB 457) and a Double-Saturation Method

2001 ◽  
Vol 21 (12) ◽  
pp. 1493-1503 ◽  
Author(s):  
Jacques Delforge ◽  
Michel Bottlaender ◽  
Christian Loc'h ◽  
Frédéric Dolle ◽  
André Syrota
Keyword(s):  
Dopamine Receptors ◽  
Quantitative Estimation ◽  
Temporal Cortex ◽  
D2 Receptor ◽  
Experimental Protocol ◽  
D2 Dopamine Receptors ◽  
High Affinity ◽  
Receptor Sites ◽  
Receptor Concentration ◽  
Saturation Method

The potential of positron emission tomography for the quantitative estimation of receptor concentration in extrastriatal regions has been limited in the past because of the low density of the D2 receptor sites in these regions and the insufficient affinity of the most widely used radioligands for dopamine receptors. The new method described in this paper permits the estimate of the D2 receptor concentration in the extrastriatal regions using a two-injection protocol and FLB 457, a ligand with a high affinity (20 pmol/L in vitro) with D2 dopamine receptors. This approach is not valid for the striatal regions because some hypotheses cannot be verified (because of the high receptor concentration in these regions). The experimental protocol includes two injections with ligand doses designed to significantly occupy the extrastriatal receptor sites (≈ 90%), while leaving less than 60% of the receptor sites occupied by the ligand in the striatal regions. The results obtained using this double-saturation method are in line with the concentration estimates previously obtained using the multiinjection approach. The receptor concentration is 2.9 ± 0.5 pmol/mL in the thalamus, 1.0 ± 0.2 pmol/mL in the temporal cortex, and 0.35 ± 0.13 pmol/mL in the occipital cortex. This study provides new arguments supporting the presence of a small receptor-site concentration in the cerebellum, estimated at 0.35 ± 0.16 pmol/mL The simplicity of the calculation used to estimate the receptor concentration lends itself easily to parametric imaging. The receptor concentration is estimated pixel by pixel, without filtering. This method permits estimation of the extrastriatal D2 receptor concentration using an experimental protocol that can easily be used in patient studies (i.e., single experiment, no blood sampling, short experiment duration).

scholarly journals Evidence that hindbrain astrocytes in the rat detect low glucose with a glucose transporter 2-phospholipase C-calcium release mechanism

2020 ◽  
Vol 318 (1) ◽  
pp. R38-R48 ◽  
Author(s):  
Richard C. Rogers ◽  
Susan J. Burke ◽  
J. Jason Collier ◽  
Sue Ritter ◽  
Gerlinda E. Hermann
Keyword(s):  
Phospholipase C ◽  
Calcium Imaging ◽  
Calcium Release ◽  
Glucose Sensor ◽  
Essential Feature ◽  
Release Mechanism ◽  
Calcium Signal ◽  
Imaging Studies ◽  
Glucose Transporter 2 ◽  
Low Glucose

Astrocytes generate robust cytoplasmic calcium signals in response to reductions in extracellular glucose. This calcium signal, in turn, drives purinergic gliotransmission, which controls the activity of catecholaminergic (CA) neurons in the hindbrain. These CA neurons are critical to triggering glucose counter-regulatory responses (CRRs) that, ultimately, restore glucose homeostasis via endocrine and behavioral means. Although the astrocyte low-glucose sensor involvement in CRR has been accepted, it is not clear how astrocytes produce an increase in intracellular calcium in response to a decrease in glucose. Our ex vivo calcium imaging studies of hindbrain astrocytes show that the glucose type 2 transporter (GLUT2) is an essential feature of the astrocyte glucosensor mechanism. Coimmunoprecipitation assays reveal that the recombinant GLUT2 binds directly with the recombinant Gq protein subunit that activates phospholipase C (PLC). Additional calcium imaging studies suggest that GLUT2 may be connected to a PLC-endoplasmic reticular-calcium release mechanism, which is amplified by calcium-induced calcium release (CICR). Collectively, these data help outline a potential mechanism used by astrocytes to convert information regarding low-glucose levels into intracellular changes that ultimately regulate the CRR.

Sign in / Sign up

Export Citation Format

Share Document