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PMID: 12122070 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

D1 dopamine receptor regulation of microtubule-associated protein-2 phosphorylation in developing cerebral cortical neurons.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 22 ·No. 14 ·2002-07-15 ·Pages 6092-105

Song ZM, Undie AS, Koh PO, Fang YY, Zhang L, Dracheva S, Sealfon SC, Lidow MS

Abstract

This study addresses the hypothesis that the previously described capacity of D1 dopamine receptors (D1Rs) to regulate dendritic growth in developing cortical neurons may involve alterations in the phosphorylation state of microtubule-associated protein-2 (MAP2). The changes in phosphorylation of this protein are known to affect its ability to stabilize the dendritic cytoskeleton. The study involved two systems: primary cultures of mouse cortical neurons grown in the presence of the D1R agonists, SKF82958 or A77636, and the cortex of neonatal transgenic mice overexpressing the D1A subtype of D1R. In both models, a decrease in dendritic extension corresponded with an elevation in MAP2 phosphorylation. This phosphorylation occurred on all three amino acid residues examined in this study: serine, threonine, and tyrosine. In cultured cortical neurons, D1R stimulation-induced increase in MAP2 phosphorylation was blocked by the protein kinase A (PKA) inhibitor, H-89, and mimicked by the PKA activator, S(p)-cAMPS. This indicates that D1Rs modulate MAP2 phosphorylation through PKA-associated intracellular signaling pathways. We also observed that the elevations in MAP2 phosphorylation in neuronal cultures in the presence of D1R agonists (or S(p)-cAMPS) were maintained for a prolonged time (up to at least 96 hr). Moreover, MAP2 phosphorylation underwent a substantial increase between 24 and 72 hr of exposure to these drugs. Our findings are consistent with the idea that D1Rs can modulate growth and maintenance of dendrites in developing cortical cells by regulating the phosphorylation of MAP2. In addition, our observations suggest that MAP2 phosphorylation by long-term activation of D1Rs (and PKA) can be divided into two phases: the initial approximately 24-hr-long phase of a relatively weak elevation in phosphorylation and the delayed phase of a much more robust phosphorylation increase taking place during the next approximately 48 hr.

MeSH Terms
Animals Animals, Newborn Cells, Cultured Cerebral Cortex/cytology Cyclic AMP-Dependent Protein Kinases/drug effects,metabolism Dendrites/drug effects,physiology,ultrastructure Dopamine Agonists/pharmacology Dose-Response Relationship, Drug Enzyme Activators/pharmacology Enzyme Inhibitors/pharmacology Frontal Lobe/cytology Mice Mice, Transgenic Microtubule-Associated Proteins/metabolism Neurites/drug effects,ultrastructure Neurons/cytology,drug effects,metabolism Phosphorylation/drug effects Receptors, Dopamine D1/agonists,genetics,metabolism Serine/metabolism Signal Transduction Threonine/metabolism Time Factors Tyrosine/metabolism
Chemicals
Dopamine Agonists Enzyme Activators Enzyme Inhibitors Microtubule-Associated Proteins Receptors, Dopamine D1 dopamine D1A receptor Threonine Tyrosine Serine Cyclic AMP-Dependent Protein Kinases
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Song Z-M
Department of Oral and Craniofacial Biological Sciences, University of Maryland, Baltimore, Maryland 21201, USA.
Undie A S
Koh P O
Fang Y-Y
Zhang L
Dracheva S
Sealfon S C
Lidow M S
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
20026478
Published
2002-07-15
Pages
6092-105
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6757946
Subset
IM
Grants
NIDA NIH HHS · R01 DA008057 · United States
NIDA NIH HHS · DA08057 · United States
NIMH NIH HHS · MH44866 · United States
External Links
PubMed source DOI: 20026478 PMC Full Text View journal details
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