Ropinirole and Pramipexole Promote Structural Plasticity in Human iPSC-Derived Dopaminergic Neurons via BDNF and mTOR Signaling

The antiparkinsonian ropinirole and pramipexole are D3 receptor- (D3R-) preferring dopaminergic (DA) agonists used as adjunctive therapeutics for the treatment resistant depression (TRD). While the exact antidepressant mechanism of action remains uncertain, a role for D3R in the restoration of impaired neuroplasticity occurring in TRD has been proposed. Since D3R agonists are highly expressed on DA neurons in humans, we studied the effect of ropinirole and pramipexole on structural plasticity using a translational model of human-inducible pluripotent stem cells (hiPSCs). Two hiPSC clones from healthy donors were differentiated into midbrain DA neurons. Ropinirole and pramipexole produced dose-dependent increases of dendritic arborization and soma size after 3 days of culture, effects antagonized by the selective D3R antagonists SB277011-A and S33084 and by the mTOR pathway kinase inhibitors LY294002 and rapamycin. All treatments were also effective in attenuating the D3R-dependent increase of p70S6-kinase phosphorylation. Immunoneutralisation of BDNF, inhibition of TrkB receptors, and blockade of MEK-ERK signaling likewise prevented ropinirole-induced structural plasticity, suggesting a critical interaction between BDNF and D3R signaling pathways. The highly similar profiles of data acquired with DA neurons derived from two hiPSC clones underpin their reliability for characterization of pharmacological agents acting via dopaminergic mechanisms.

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Faculty Opinions recommendation of Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13482957.14860058 ◽

2012 ◽

Author(s):

Domenico Alvaro ◽

Vincenzo Cardinale

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Genetic Characterization ◽

Therapeutic Targets

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Generation and characterization of a human iPSC line SANi006-A from a Gray Platelet Syndrome patient

Stem Cell Research ◽

10.1016/j.scr.2021.102443 ◽

2021 ◽

pp. 102443

Author(s):

Cathelijn E.M. Aarts ◽

Eszter Varga ◽

Steven Webbers ◽

Judy Geissler ◽

Marieke von Lindern ◽

...

Keyword(s):

Syndrome Patient ◽

Ipsc Line ◽

Gray Platelet Syndrome ◽

Human Ipsc

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Characterization of the isolated rat flexor digitorum brevis for the study of skeletal muscle phosphorylase kinase phosphorylation.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)61495-4 ◽

1987 ◽

Vol 262 (7) ◽

pp. 3227-3238

Author(s):

C.A. Pickett-Gies ◽

R.C. Carlsen ◽

L.J. Anderson ◽

K.L. Angelos ◽

D.A. Walsh

Keyword(s):

Skeletal Muscle ◽

Phosphorylase Kinase ◽

Flexor Digitorum Brevis ◽

Muscle Phosphorylase ◽

Flexor Digitorum ◽

Kinase Phosphorylation ◽

Isolated Rat

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Development of off-line and on-line capillary electrophoresis methods for the screening and characterization of adenosine kinase inhibitors and substrates

Electrophoresis ◽

10.1002/elps.200500944 ◽

2006 ◽

Vol 27 (12) ◽

pp. 2505-2517 ◽

Cited By ~ 33

Author(s):

Jamshed Iqbal ◽

Joachim C. Burbiel ◽

Christa E. Müller

Keyword(s):

Capillary Electrophoresis ◽

Kinase Inhibitors ◽

Adenosine Kinase ◽

On Line

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Characterization of excretory–secretory products from protoscoleces of Echinococcus granulosus and evaluation of their potential for immunodiagnosis of human cystic echinococcosis

Parasitology ◽

10.1017/s0031182004005670 ◽

2004 ◽

Vol 129 (3) ◽

pp. 371-378 ◽

Cited By ~ 20

Author(s):

D. CARMENA ◽

J. MARTÍNEZ ◽

A. BENITO ◽

J. A. GUISANTES

Keyword(s):

Echinococcus Granulosus ◽

Cystic Echinococcosis ◽

Secretory Protein ◽

Major Protein ◽

Healthy Donors ◽

Secretory Products ◽

Protein Components ◽

Human Cystic Echinococcosis

This study describes, for the first time, the characterization of excretory–secretory antigens (ES-Ag) from Echinococcus granulosus protoscoleces, evaluating their usefulness in the immunodiagnosis of human cystic echinococcosis. ES-Ag were obtained from the first 50 h maintenance of protoscoleces in vitro. This preparation contained over 20 major protein components which could be distinguished by 1-dimensional SDS–PAGE with apparent masses between 9 and 300 kDa. The culture of of protoscoleces from liver produced a greater variety of excretory–secretory protein components than those from lung. Determination of enzymatic activities of secreted proteins revealed the presence of phosphatases, lipases and glucosidases, but no proteases. These findings were compared to those obtained from somatic extracts of protoscoleces and hydatid cyst fluid products. Immunochemical characterization was performed by immunoblotting with sera from individuals infected by cystic echinococcosis (n=15), non-hydatidic parasitoses (n=19), various liver diseases (n=24), lung neoplasia (n=16), and healthy donors (n=18). Antigens with apparent masses of 89, 74, 47/50, 32, and 20 kDa showed specificity for immunodiagnosis of human hydatidosis. The 89 and 74 kDa components corresponded to antigens not yet described in E. granulosus, whereas proteins of 41–43 kDa and 91–95 kDa were recognized by the majority of the non-hydatid sera studied.

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Flow cytometric quantitation and characterization of the T-lymphocyte memory response to CMV in healthy donors

Cytotherapy ◽

10.1080/146532402317251509 ◽

2002 ◽

Vol 4 (1) ◽

pp. 29-40 ◽

Cited By ~ 15

Author(s):

N. Hensel ◽

J.J. Melenhorst ◽

K. Bradstock ◽

A.P. Schwarer ◽

R. Eniafe ◽

...

Keyword(s):

T Lymphocyte ◽

Memory Response ◽

Flow Cytometric ◽

Healthy Donors

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Generation and characterization of a human iPSC line from an ALS patient carrying the Q66K-MATR3 mutation

Stem Cell Research ◽

10.1016/j.scr.2018.10.011 ◽

2018 ◽

Vol 33 ◽

pp. 146-150 ◽

Cited By ~ 1

Author(s):

Daniele Pollini ◽

Rosa Loffredo ◽

Marina Cardano ◽

Luciano Conti ◽

Serena Lattante ◽

...

Keyword(s):

Ipsc Line ◽

Human Ipsc

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Hypertonicity-induced phosphorylation and nuclear localization of the transcription factor TonEBP

AJP Cell Physiology ◽

10.1152/ajpcell.2001.280.2.c248 ◽

2001 ◽

Vol 280 (2) ◽

pp. C248-C253 ◽

Cited By ~ 90

Author(s):

Stephen C. Dahl ◽

Joseph S. Handler ◽

H. Moo Kwon

Keyword(s):

Transcription Factor ◽

Nuclear Localization ◽

Kinase Inhibitors ◽

Dependent Manner ◽

Binding Assays ◽

P38 Inhibitor ◽

Vitro Binding ◽

Compatible Osmolytes

The accumulation of compatible osmolytes during osmotic stress is observed in virtually all organisms. In mammals, the hypertonicity-induced expression of osmolyte transporters and synthetic enzymes is conferred by the presence of upstream tonicity-responsive enhancer (TonE) sequences. Recently, we described the cloning and initial characterization of TonE-binding protein (TonEBP), a transcription factor that translocates to the nucleus and associates with TonE sequences in a tonicity-dependent manner. We now report that hypertonicity induces an increase in TonEBP phosphorylation that temporally correlates with increased nuclear localization of the molecule. TonEBP phosphorylation is not affected by a number of kinase inhibitors, including the p38 inhibitor SB-203580. In addition, in vitro binding assays show that the association of TonEBP with TonE sequences is not affected by phosphorylation. Thus TonEBP phosphorylation is an early step in the response of cells to hypertonicity and may be required for nuclear import or retention.

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