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Received for publication May 4, 2004.
Revised July 28, 2004.
Accepted for publication July 29, 2004.
A brain dopamine receptor that modulates phosphatidylinositol metabolism via the activation of PLC 
has been previously described. The present study aims to define the down stream signaling cascade initiated by the PI-linked dopamine receptor. Incubation of rat brain frontal cortical slices with SKF83959, a recently identified selective agonist of the PI-linked D1 -like dopamine receptor, elicited transient time-and dose-dependent stimulations of cdk5 and CaMKII activities. The stimulation of these kinases is blocked by 20 µM SCH23390 or the PLC antagonist, U-73122, and is attenuated by the protein kinase inhibitor, calphostin C or by the intracellular calcium chelator BAPTA, indicating, that SKF83959 stimulates cdk5 and CaMK II activities via a PI-linked D1-like dopamine receptor and PLC and is dependent on PKC and calcium. Although cdk5 and CaMK II is physically associated in native brain tissue, no change in this association was observed in response to SKF 83959 stimulation, or to the inhibition of either cdk5 by roscovitine or of CaMK, by KN93, suggesting that SKF83959-mediated stimulation of cdk5 or CaMK II is independent of the other kinase and that the association of the two kinases is not modulated by change of kinase activity. Moreover, we found that cdk5 phosphorylates DARPP-32 (Thr-75) while CaMK II is responsible for the activation of CREB in response to SKF83959 stimulation. The present data provides the first insight into the signaling mechanism for the PI-linked dopamine receptor. This information, in turn, may help in exploring the functional consequences of stimulation of this brain receptor.
Key words:
Dopamine, Gq/11 family, Phospholipase C's, IP3/DAG, Protein Kinase C, Phosphorylation/Dephosphorylation, CREB, Synaptic plasticity
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