Constitutive Activity of a G Protein-Coupled Receptor, DRD1, Contributes to Human Cerebral Organoid Formation.

07:00 EST 13th February 2020 | BioPortfolio

Summary of "Constitutive Activity of a G Protein-Coupled Receptor, DRD1, Contributes to Human Cerebral Organoid Formation."

The intricate balance of neural stem cell (NSC) amplification and neurogenesis is central to nervous system development. Dopamine D1 receptor (DRD1) is a typical G protein-coupled receptor (GPCR) mainly expressed in neurogenic area, with high constitutive activity. The receptor appears in the embryonic period before the formation of mature synaptic contacts, which indicates that dopamine receptor and its constitutive activity play crucial roles in the embryonic brain development. Here, we found that DRD1 was enriched in human NSCs. Inhibition of the receptor activity by its inverse agonists promoted human NSCs proliferation and impeded it differentiation. These results were also mimicked by genetic knockdown of DRD1, which also blocked the effects of inverse agonists, suggesting a receptor-dependent manner. More interestingly, knock-in A229T mutant with reduced DRD1 constitutive activity by CRISPR-Cas9 genome editing technology resulted into increased endogenous human NSCs proliferation. These results were well reproduced in human cerebral organoids and inhibition of the DRD1 constitutive activity by its inverse agonists induced the expansion and folding of human cerebral organoids. The anatomic analysis uncovered that decreasing the constitutive activity of DRD1 by its inverse agonists promoted the NSCs proliferation and maintenance that led to hindered cortical neurogenesis. Further mechanistic studies revealed that the PKC-CBP pathway was involved in the regulation by DRD1. Thus, our findings indicate that the constitutive activity of DRD1 and possibly other GPCRs plays an important role in the development of human nervous system. © AlphaMed Press 2020 SIGNIFICANCE
In the current study, the authors first demonstrated a potential role of DRD1 constitutive activity for the regulation of neurogenesis in human brain development. Inhibiting the constitutive activity of the DRD1 promoted human NSC amplification and thus induced expansion and folding of human cerebral organoids, thereby impeded the process of neurogenesis. The DRD1 mediates its action on NSCs partially through down-regulating the genesis of neurons in a CBP/p300-dependent fashion by reducing the level of PKC phosphorylation. This study also provides another insight that there might be strategies to effectively control the time of neural precursor (NP) amplification or neuron transition by flexibly and precisely regulating the constitutive activity of DRD1 and modulating the multiple stages of adult NSC development in a single therapeutic strategy is possible to fight against age-related decline in hippocampal NSC.


Journal Details

This article was published in the following journal.

Name: Stem cells (Dayton, Ohio)
ISSN: 1549-4918


DeepDyve research library

PubMed Articles [34098 Associated PubMed Articles listed on BioPortfolio]

Constitutive activity of 5-HT receptors: Factual analysis.

The constitutive activity of different serotonin receptors (5-HTRs) toward intracellular signaling pathways has been proposed to have physiological and pathological importance. Inverse agonists block ...

A adenosine receptor activation mechanisms: molecular dynamics analysis of inactive, active, and fully active states.

We investigated the Gi-coupled A adenosine receptor (AAR) activation mechanism by running 7.2 µs of molecular dynamics (MD) simulations. Based on homology to G protein-coupled receptor (GPCR) struct...

Discovery of Benzamidine- and 1-Aminoisoquinoline-Based Human MAS-Related G-Protein-Coupled Receptor X1 (MRGPRX1) Agonists.

Mas-related G-protein-coupled receptor X1 (MRGPRX1) is a human sensory neuron-specific receptor and has been actively investigated as a therapeutic target for the treatment of pain. By use of two HTS ...

G-protein coupled receptor 40 expression in human melanoma - correlation with tumor thickness, AJCC stage and survival.

In melanoma, preclinical data suggests a possible role of polyunsaturated fatty acids inhibiting cell growth. A new target molecule for free fatty acids, the G-protein coupled receptor GPR40, was iden...

G-Protein/Receptor Inhibitors as Blockers of Receptor Signaling.

This paper describes the behavior of binding and functional receptor systems where an antagonist of the receptor/G protein binding reaction is added as a blocker of agonist-induced receptor function. ...

Clinical Trials [12803 Associated Clinical Trials listed on BioPortfolio]

Expression of G-protein Coupled Receptor 120 (GPR120) Receptor in Adipose Tissue of German Diabetes Center (GDC) Cohort Subjects

G-protein coupled receptor 120 (GPR120) is a G-protein-coupled receptor whose endogenous ligands have been identified as long-chain fatty acids. Recently, it has been shown that GPR120 exp...

GPR 119 Stimulated GLP-1 Secretion

The purpose of this study is to evaluate the impact of different ligands of GPR 119 (a G protein-coupled receptor in the intestine) on the secretion of the incretin hormones, GLP-1 and GIP...

Effect of Gene Variants on Dopamine Receptor Natriuretic Responses

Hypothesis to be tested: Dopamine D1-like receptor-induced natriuresis is impaired in humans with G protein-related kinase 4 gene variants. Our research group has discovered a D1 receptor...

Effect of Dietary Oils as G-protein-coupled Receptor Agonists on Glucose Tolerance

Agonistic activation of fat metabolite responsive G-protein-coupled receptors (GPCR) has been linked to improved glucose metabolism through increased glucose-stimulated-insulin-secreting (...

Protein S Activity in Women With Unexplained Infertility

This study will add: Finding out an association between Protein S activity and unexplained female infertility. Aim: Study hypothesis: In women with unexplained infertility ...

Medical and Biotech [MESH] Definitions

A receptor activity-modifying protein that is a subunit of specific G-PROTEIN COUPLED RECEPTORS. The CALCITONIN GENE-RELATED PEPTIDE RECEPTOR is formed from a dimer of this protein and CALCITONIN RECEPTOR-LIKE PROTEIN, while an isoform of the ISLET AMYLOID POLYPEPTIDE RECEPTOR is formed from this protein dimerizing with the CALCITONIN RECEPTOR.

A ubiquitously expressed G-protein-coupled receptor kinase subtype that has specificity for the agonist-occupied form of BETA-ADRENERGIC RECEPTORS and a variety of other G-PROTEIN-COUPLED RECEPTORS. Although it is highly homologous to G-PROTEIN-COUPLED RECEPTOR KINASE 2, it is not considered to play an essential role in regulating myocardial contractile response.

A family of serine-threonine kinases that are specific for G-PROTEIN-COUPLED RECEPTORS. They are regulatory proteins that play a role in G-protein-coupled receptor densensitization.

G-protein-coupled cell surface receptors for ADRENOMEDULLIN. They are formed by the heterodimerization of CALCITONIN RECEPTOR-LIKE PROTEIN and either RECEPTOR ACTIVITY-MODIFYING PROTEIN 2 or RECEPTOR ACTIVITY-MODIFYING PROTEIN 3.

G-protein coupled receptors that are formed through the dimerization of the CALCITONIN RECEPTOR with a RECEPTOR ACTIVITY-MODIFYING PROTEIN. Their affinity for ISLET AMYLOID POLYPEPTIDE is dependent upon which of several receptor activity-modifying protein subtypes they are bound to.

Quick Search

DeepDyve research library

Relevant Topics

Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...

Stem Cells
Track and monitor developments in stem cell research and commercial development.  Follow the tabs above to read the latest global news, research, clinical trials on stem cells and follow companies active in the stem cell industry.  BioPort...

Searches Linking to this Article