RT Journal Article
SR Electronic
T1 D1 Dopamine Receptor Regulation of Microtubule-Associated Protein-2 Phosphorylation in Developing Cerebral Cortical Neurons
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 6092
OP 6105
DO 10.1523/JNEUROSCI.22-14-06092.2002
VO 22
IS 14
A1 Z.-M. Song
A1 A. S. Undie
A1 P. O. Koh
A1 Y.-Y. Fang
A1 L. Zhang
A1 S. Dracheva
A1 S. C. Sealfon
A1 M. S. Lidow
YR 2002
UL http://www.jneurosci.org/content/22/14/6092.abstract
AB 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, Sp-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 Sp-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 ∼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 ∼48 hr.