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First published on January 17, 2008; DOI: 10.1124/mol.107.042580

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Received for publication October 11, 2007.
Revised December 22, 2007.
Accepted for publication January 17, 2008.

Dopamine and Ethanol Cause Translocation of {epsilon}PKC Associated with {epsilon}RACK: Cross-talk Between PKA and PKC Signaling Pathways

Lina Yao 1*, Peidong Fan 1, Zhan Jiang 1, Adrienne Gordon 2, Daria Mochly-Rosen 3, Ivan Diamond 1

1 CV Therapeutics, Inc. 2 Ernest Gallo Clinic and Research Center 3 Stanford University

* Address correspondence to: E-mail: lina.yao{at}cvt.com

Abstract

Previously we found that neural responses to ethanol and the dopamine D2 receptor (D2) agonist NPA involve both epsilon protein kinase C ({epsilon}PKC) and cAMP-dependent protein kinase A (PKA). However, little is known about the mechanism underlying ethanol- and D2-mediated activation of {epsilon}PKC and the relationship to PKA activation. In the present study, we used a new {epsilon}PKC antibody, 14E6, that selectively recognizes active {epsilon}PKC when not bound to its anchoring protein {epsilon}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 {epsilon}PKC and also induced translocation of both {epsilon}PKC and its anchoring protein, {epsilon}RACK to a new cytosolic site. The selective {epsilon}PKC agonist, pseudo-{epsilon}RACK, activated {epsilon}PKC but did not cause translocation of the {epsilon}PKC/{epsilon}RACK complex to the cytosol. These data suggest a step-wise activation and translocation of {epsilon}PKC following NPA or ethanol treatment where {epsilon}PKC first translocates and binds to its RACK and subsequently the {epsilon}PKC/{epsilon}RACK complex translocates to a new subcellular site. Direct activation of PKA by Sp-cAMPS, PGE1 or the adenosine A2A receptor is sufficient to cause {epsilon}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 {epsilon}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.


Key words: Dopamine, Protein Kinase A, Protein Kinase C, Alcohols


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