Stimulation of L-type calcium channels increases tyrosine hydroxylase and dopamine in ventral midbrain cells induced from somatic cells.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
/ pharmacology
Calcium
/ metabolism
Calcium Channels, L-Type
/ metabolism
Cell Differentiation
Cell Line
Cell Shape
/ drug effects
Dopamine
/ metabolism
Dopaminergic Neurons
/ cytology
Electrophysiological Phenomena
Hepatocyte Nuclear Factor 3-beta
/ metabolism
Humans
Mesencephalon
/ cytology
Neural Stem Cells
/ cytology
Transcriptome
/ genetics
Tyrosine 3-Monooxygenase
/ metabolism
cell biology
induced pluripotent stem cells (iPSCs)
nervous system
neural differentiation
neural induction
Journal
Stem cells translational medicine
ISSN: 2157-6580
Titre abrégé: Stem Cells Transl Med
Pays: England
ID NLM: 101578022
Informations de publication
Date de publication:
Jun 2020
Jun 2020
Historique:
received:
16
08
2018
accepted:
03
01
2020
pubmed:
11
3
2020
medline:
2
7
2021
entrez:
11
3
2020
Statut:
ppublish
Résumé
Making high-quality dopamine (DA)-producing cells for basic biological or small molecule screening studies is critical for the development of novel therapeutics for disorders of the ventral midbrain. Currently, many ventral midbrain assays have low signal-to-noise ratio due to low levels of cellular DA and the rate-limiting enzyme of DA synthesis, tyrosine hydroxylase (TH), hampering discovery efforts. Using intensively characterized ventral midbrain cells derived from human skin, which demonstrate calcium pacemaking activity and classical electrophysiological properties, we show that an L-type calcium agonist can significantly increase TH protein levels and DA content and release. Live calcium imaging suggests that it is the immediate influx of calcium occurring simultaneously in all cells that drives this effect. Genome-wide expression profiling suggests that L-type calcium channel stimulation has a significant effect on specific genes related to DA synthesis and affects expression of L-type calcium receptor subunits from the CACNA1 and CACNA2D families. Together, our findings provide an advance in the ability to increase DA and TH levels to improve the accuracy of disease modeling and small molecule screening for disorders of the ventral midbrain, including Parkinson's disease.
Identifiants
pubmed: 32154672
doi: 10.1002/sctm.18-0180
pmc: PMC7214648
doi:
Substances chimiques
Calcium Channels, L-Type
0
Hepatocyte Nuclear Factor 3-beta
135845-92-0
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
71145-03-4
Tyrosine 3-Monooxygenase
EC 1.14.16.2
Calcium
SY7Q814VUP
Dopamine
VTD58H1Z2X
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
697-712Informations de copyright
© 2020 The Authors. Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.
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