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The insulin and dopaminergic systems in the brain are associated with schizophrenia and Parkinson's disease with respect to etiology and treatment. The present study investigated the crosstalk between the insulin receptor (IR) and dopamine receptor and found that insulin stimulation selectively inhibits signaling of D3R in a PKCβII‐dependent manner. Upon insulin stimulation, E3 ligase enzyme Mdm2 moves out of the nucleus to ubiquitinate PKCβII. Subsequently, ubiquitinated PKCβII translocates to the cell membrane and interacts with D3R in a phosphorylation‐dependent manner at S229/257, resulting in the attenuation of D3R signaling and initiating clathrin‐mediated endocytosis and downregulation. Considering that both IR and D3R are closely related to some neuropsychosis, this study could provide new molecular insight into the etiology of the disorder. [ABSTRACT FROM AUTHOR]

Dopamine D2 receptor (D2R) has been shown to activate extracellular signal‐regulated kinases (ERKs) via distinct pathways dependent on either G‐protein or β‐arrestin. However, there has not been a systematic study of the regulatory process of D2R‐mediated ERKs activation by G protein‐ versus β‐arrestin‐dependent signaling since D2R stimulation of ERKs reflects the simultaneous action of both pathways. Here, we investigated that differential regulation of D2R‐mediated ERKs activation via these two pathways. Our results showed that G protein‐dependent ERKs activation was transient, rapid, reached maximum level at around 2 min, and importantly, the activated ERKs were entirely confined to the cytoplasm. In contrast, β‐arrestin‐dependent ERKs activation was more sustained, slower, reached maximum level at around 10 min, and phosphorylated ERKs translocated into the nucleus. Src was found to be commonly involved in both the G protein‐ and β‐arrestin‐dependent pathway‐mediated ERKs activation. Pertussis toxin Gi/o inhibitor, GRK2‐CT, AG1478 epidermal growth factor receptor inhibitor, and wortmannin phosphoinositide 3‐kinase inhibitor all blocked G protein‐dependent ERKs activation. In contrast, GRK2 and β‐Arr2 played a main role in β‐arrestin‐dependent ERKs activation. Receptor endocytosis showed minimal effect on the activation of ERKs mediated by both pathways. Furthermore, we found that the formation of a complex composed of phospho‐ERKs, β‐Arr2, and importinβ1 promoted the nuclear translocation of activated ERKs. The differential regulation of various cellular components, as well as temporal and spatial patterns of ERKs activation via these two pathways, suggest the existence of distinct physiological outcomes. [ABSTRACT FROM AUTHOR]

In this study, we aimed to demonstrate the antidiabetic potential of (E)-N-(4-(3-(5-bromo-4-hydroxy-2-methoxyphenyl)acryloyl) phenyl)-4- tert -butylbenzamide (SN158) through peroxisome proliferator-activated receptor (PPAR)-α/γ dual activation. SN158 interacted with both PPARα and PPARγ, and increased their transcriptional activities. Simultaneously, SN158 treatment led to an increase in adipogenic differentiation of 3T3-L1 preadipocytes and fatty acid oxidation in hepatocytes. In addition, glucose uptake in myotubes was significantly increased by SN158 treatment. Finally, SN158 significantly lowered the plasma levels of glucose, triglycerides, and free fatty acids in ob/ob mice without severe weight gain and hepatomegaly. These results suggest that SN158 can be useful as a potential therapeutic agent against type 2 diabetes and related metabolic disorders by alleviating glucose and lipid abnormalities. [ABSTRACT FROM AUTHOR]

The insulin and dopaminergic systems in the brain are associated with schizophrenia and Parkinson's disease with respect to etiology and treatment. The present study investigated the crosstalk between the insulin receptor (IR) and dopamine receptor and found that insulin stimulation selectively inhibits signaling of D 3 R in a PKCβII-dependent manner. Upon insulin stimulation, E3 ligase enzyme Mdm2 moves out of the nucleus to ubiquitinate PKCβII. Subsequently, ubiquitinated PKCβII translocates to the cell membrane and interacts with D 3 R in a phosphorylation-dependent manner at S229/257, resulting in the attenuation of D 3 R signaling and initiating clathrin-mediated endocytosis and downregulation. Considering that both IR and D 3 R are closely related to some neuropsychosis, this study could provide new molecular insight into the etiology of the disorder., (© 2024 Federation of European Biochemical Societies.)

Dopamine D 2 receptor (D 2 R) has been shown to activate extracellular signal-regulated kinases (ERKs) via distinct pathways dependent on either G-protein or β-arrestin. However, there has not been a systematic study of the regulatory process of D 2 R-mediated ERKs activation by G protein- versus β-arrestin-dependent signaling since D 2 R stimulation of ERKs reflects the simultaneous action of both pathways. Here, we investigated that differential regulation of D 2 R-mediated ERKs activation via these two pathways. Our results showed that G protein-dependent ERKs activation was transient, rapid, reached maximum level at around 2 min, and importantly, the activated ERKs were entirely confined to the cytoplasm. In contrast, β-arrestin-dependent ERKs activation was more sustained, slower, reached maximum level at around 10 min, and phosphorylated ERKs translocated into the nucleus. Src was found to be commonly involved in both the G protein- and β-arrestin-dependent pathway-mediated ERKs activation. Pertussis toxin Gi/o inhibitor, GRK2-CT, AG1478 epidermal growth factor receptor inhibitor, and wortmannin phosphoinositide 3-kinase inhibitor all blocked G protein-dependent ERKs activation. In contrast, GRK2 and β-Arr2 played a main role in β-arrestin-dependent ERKs activation. Receptor endocytosis showed minimal effect on the activation of ERKs mediated by both pathways. Furthermore, we found that the formation of a complex composed of phospho-ERKs, β-Arr2, and importinβ1 promoted the nuclear translocation of activated ERKs. The differential regulation of various cellular components, as well as temporal and spatial patterns of ERKs activation via these two pathways, suggest the existence of distinct physiological outcomes., (© 2023 Federation of European Biochemical Societies.)

[This corrects the article DOI: 10.1039/C8MD00237A.].

The dopamine D 3 receptor (D 3 R) is a proven therapeutic target for the treatment of neurological and neuropsychiatric disorders. In particular, D 3 R-selective ligands that can eliminate side effects associated with dopamine D 2 receptor (D 2 R) therapeutics have been validated. However, the high homology in signaling pathways and the sequence similarity between D 2 R and D 3 R have rendered the development of D 3 R-selective ligands challenging. Herein, we designed and synthesized a series of piperazine-phthalimide bitopic ligands based on a fragment-based and molecular docking inspired design. Compound 9i was identified as the most selective D 3 R ligand among these bitopic ligands. Its selectivity was improved compared to reference compounds 1 and 2 by 9- and 2-fold, respectively, and it was 21-fold more potent than compound 2 . Molecular docking demonstrated that the orientation of Leu 2.64 and Phe 7.39 and the packing at the junction of helices may affect the specificity for D 3 R over D 2 R. Functional evaluation revealed that D 3 R-selective ligand 9i displayed a subpicomolar agonist activity at D 3 R with a 199-fold increase in potency compared to quinpirole. These results may be useful for the fragment-based design of bitopic compounds as selective D 3 R ligands.