betagamma Dimers mediate synergy of dopamine D2 and adenosine A2 receptor-stimulated PKA signaling and regulate ethanol consumption.
Dopamine release is activated by ethanol and addicting drugs, but molecular mechanisms linking dopaminergic signaling to neuronal responses and drinking behavior are poorly understood. We report that dopamine-D2 receptors induce PKA Calpha translocation and increase CRE-regulated gene expression. Ethanol also activates PKA signaling. Subthreshold concentrations of the D2 agonist NPA and ethanol, without effect alone, together cause synergistic PKA translocation and CRE-mediated gene transcription. D2 or adenosine A2 receptor blockade, pertussis toxin, Rp-cAMPS, or overexpression of dominant-negative peptides that sequester betagamma dimers prevent synergy. Importantly, overexpression of a betagamma inhibitor peptide in the nucleus accumbens strikingly reduces sustained alcohol consumption. We propose that synergy of D2 and A2 confers ethanol hypersensitivity and that betagamma dimers are required for voluntary drinking.
Yao
Lina
L
Ernest Gallo Clinic and Research Center, San Francisco, CA 94110, USA.
Arolfo
Maria Pia
MP
Dohrman
Douglas P
DP
Jiang
Zhan
Z
Fan
Peidong
P
Fuchs
Sara
S
Janak
Patricia H
PH
Gordon
Adrienne S
AS
Diamond
Ivan
I
D000256:Adenoviridae / Q000235:genetics; D000428:Alcohol Drinking; D000818:Animals; D000831:Animals, Newborn; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015153:Blotting, Western; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D019281:Dimerization; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D016193:G1 Phase; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006624:Hippocampus / Q000166:cytology; D007150:Immunohistochemistry; D019426:Integrases / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D018613:Microscopy, Confocal; D008954:Models, Biological; D010455:Peptides / Q000737:chemistry; D037342:Pertussis Toxin; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D051571:Protein Kinase C-alpha; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D013347:Subcellular Fractions; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D014764:Viral Proteins / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
C425777:10,11-dihydroxy-N-n-propylnorapomorphine; D018491:Dopamine Agonists; D007527:Isoenzymes; D010455:Peptides; D017448:Receptors, Dopamine D2; D018047:Receptors, Purinergic P1; D014764:Viral Proteins; D010566:Virulence Factors, Bordetella; D000431:Ethanol; D000242:Cyclic AMP; D008156:Luciferases; D037342:Pertussis Toxin; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; C045073:Cre recombinase; D019426:Integrases; D001058:Apomorphine