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Dopamine and Ethanol Cause Translocation of PKC Associated with RACK: Cross-Talk between cAMP-Dependent Protein Kinase A and Protein Kinase C Signaling Pathways

CV Therapeutics, Inc., Palo Alto, California (L.Y., P.F., Z.J., I.D.); Ernest Gallo Clinic and Research Center, Emeryville, California (L.Y., A.G., I.D.); Departments of Neurology (L.Y., I.D.) and Cellular and Molecular Pharmacology (I.D.), and the Neuroscience Graduate Program (I.D.), University of California, San Francisco, California; and Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California (D.M.)

We found previously that neural responses to ethanol and the dopamine D2 receptor (D2) agonist 2,10,11-trihydroxy-N-propylnorapomorphine hydrobromide (NPA) involve both protein kinase C (PKC) and cAMP-dependent protein kinase A (PKA). However, little is known about the mechanism underlying ethanol- and D2-mediated activation of PKC and the relationship to PKA activation. In the present study, we used a new PKC antibody, 14E6, that selectively recognized active PKC when not bound to its anchoring protein RACK (receptor for activated C-kinase), and PKC isozyme-selective inhibitors and activators to measure PKC translocation and catalytic activity. We show here that ethanol and NPA activated PKC and induced translocation of both PKC and its anchoring protein, RACK to a new cytosolic site. The selective PKC agonist, pseudo-RACK, activated PKC but did not cause translocation of the PKC/RACK complex to the cytosol. These data suggest a step-wise activation and translocation of PKC after NPA or ethanol treatment, where PKC first translocates and binds to its RACK and subsequently the PKC/RACK complex translocates to a new subcellular site. Direct activation of PKA by adenosine-3',5'-cyclic monophosphorothioate, Sp-isomer (Sp-cAMPS), prostaglandin E1, or the adenosine A2A receptor is sufficient to cause PKC translocation to the cytosolic compartment in a process that is dependent on PLC activation and requires PKA activity. These data demonstrate a novel cross-talk mechanism between PKC and PKA signaling systems. PKA and PKC signaling have been implicated in alcohol rewarding properties in the mesolimbic dopamine system. Cross-talk between PKA and PKC may underlie some of the behaviors associated with alcoholism.

Address correspondence to: Dr. Lina Yao, CV Therapeutics, Inc., 3172 Porter Drive, Palo Alto, CA 94304. E-mail: lina.yao{at}cvt.com