ArticleProceedings of the National Academy of Sciences of the United States of America2007
The B''/PR72 subunit mediates Ca2+-dependent dephosphorylation of DARPP-32 by protein phosphatase 2A.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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58 citing papers in PubMed, 99 citations in OpenAlex.
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- Numerous Trigger-like Interactions of Kinases/Protein Phosphatases in Human Skeletal Muscles Can Underlie Transient Processes in Activation of Signaling Pathways during Exercise.International journal of molecular sciences · 2023Review
- Hypercontractile cardiac phenotype in mice overexpressing the regulatory subunit PR72 of protein phosphatase 2A.Frontiers in cardiovascular medicine · 2023Article
- Biased holoenzyme assembly of protein phosphatase 2A (PP2A): From cancer to small molecules.The Journal of biological chemistry · 2022Review
- Precise timing of ERK phosphorylation/dephosphorylation determines the outcome of trial repetition during long-term memory formation.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Piezo1 activation attenuates thrombin-induced blebbing in breast cancer cells.Journal of cell science · 2022Article
- TRPV1 channel mediates NLRP3 inflammasome-dependent neuroinflammation in microglia.Cell death & disease · 2021Article
- High expression of protein phosphatase 2 regulatory subunit B'' alpha predicts poor outcome in hepatocellular carcinoma patients after liver transplantation.World journal of gastrointestinal oncology · 2021Article
- Protein phosphatase 2A - structure, function and role in neurodevelopmental disorders.Journal of cell science · 2021Review
- Effects of nicotine on DARPP-32 and CaMKII signaling relevant to addiction.Advances in pharmacology (San Diego, Calif.) · 2021Review
- Wolfram Syndrome: a Monogenic Model to Study Diabetes Mellitus and Neurodegeneration.Current opinion in physiology · 2020Article
- Direct Interaction of PP2A Phosphatase with GABAThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- Redox inhibition of protein phosphatase PP2A: Potential implications in oncogenesis and its progression.Redox biology · 2019Review
- The temporal profile of activity-dependent presynaptic phospho-signalling reveals long-lasting patterns of poststimulus regulation.PLoS biology · 2019Article
- Striatin-1 is a B subunit of protein phosphatase PP2A that regulates dendritic arborization and spine development in striatal neurons.The Journal of biological chemistry · 2018Article
- Detection of phasic dopamine by D1 and D2 striatal medium spiny neurons.The Journal of physiology · 2017Article
- Phosphorylation of KLC1 modifies interaction with JIP1 and abolishes the enhanced fast velocity of APP transport by kinesin-1.Molecular biology of the cell · 2017Article
- The involvement of DARPP-32 in the pathophysiology of schizophrenia.Oncotarget · 2017Review
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Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
Abstract
In dopaminoceptive neurons, dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) plays a central role in integrating the effects of dopamine and other neurotransmitters. Phosphorylation of DARPP-32 at Thr-34 by protein kinase A results in inhibition of protein phosphatase 1 (PP1), and phosphorylation at Thr-75 by Cdk5 (cyclin-dependent kinase 5) results in inhibition of protein kinase A. Dephosphorylation at Thr-34 involves primarily the Ca(2+)-dependent protein phosphatase, PP2B (calcineurin), whereas dephosphorylation of Thr-75 involves primarily PP2A, the latter being subject to control by both cAMP- and Ca(2+)-dependent regulatory mechanisms. In the present study, we have investigated the mechanism of Ca(2+)-dependent regulation of Thr-75 by PP2A. We show that the PR72 (or B'' or PPP2R3A) regulatory subunit of PP2A is highly expressed in striatum. Through the use of overexpression and down-regulation by using RNAi, we show that PP2A, in a heterotrimeric complex with the PR72 subunit, mediates Ca(2+)-dependent dephosphorylation at Thr-75 of DARPP-32. The PR72 subunit contains two Ca(2+) binding sites formed by E and F helices (EF-hands 1 and 2), and we show that the former is necessary for the ability of PP2A activity to be regulated by Ca(2+), both in vitro and in vivo. Our studies also indicate that the PR72-containing form of PP2A is necessary for the ability of glutamate acting at alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and NMDA receptors to regulate Thr-75 dephosphorylation. These studies further our understanding of the complex signal transduction pathways that regulate DARPP-32. In addition, our studies reveal an alternative intracellular mechanism whereby Ca(2+) can activate serine/threonine phosphatase activity.
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