Expression of striatal adenosine and dopamine receptors in mice deficient in the p50 subunit of NF-kappaB.
The striatal dopamine D2 receptor (D2R) and adenosine A2A receptor (A2AAR) exhibit mutually antagonistic effects through physical interactions and by differential modulation of post-receptor signaling pathways. The expression of the A2AAR and the D2R is differentially regulated by nuclear factor-kappaB (NF-kappaB). In this report, we determined the role of NF-kappaB in regulation of these receptors by comparing mice deficient in the NF-kappaB p50 subunit (p50 KO) with genetically intact B6129PF2/J (F2) mice. Quantification of adenosine receptor (AR) subtypes in mouse striatum by real time PCR, immunocytochemistry and radioligand binding assays showed more A2AAR but less A1AR in p50 KO mice as compared with F2 mice. Striata from p50 KO mice also had less D2R mRNA and [(3)H]-methylspiperone binding than did striata from F2 mice. G(alphaolf) and G(alphas) proteins, which are transducers of A2AAR signals, were also present at a higher level in striata from the p50 KO versus F2 mice. In contrast, the G(alphai1) protein, which transduces signals from the A1AR and D2R, was significantly reduced in striata from p50 KO mice. Behaviorally, p50 KO mice exhibited increased locomotor activity relative to that of F2 mice after caffeine ingestion. These data are consistent with a role for the NF-kappaB in the regulation of A1AR, A2AAR, D2R and possibly their coupling G proteins in the striatum. Dysregulation of these receptors in the striata of p50 KO mice might sensitize these animals to locomotor stimulatory action of caffeine.
Xie
Xiaobin
X
Department of Pharmacology, Southern Illinois University School of Medicine, PO Box 19629 Springfield, IL 62794-9629, United States.
Jhaveri
Krishna A
KA
Ding
Ming
M
Hughes
Larry F
LF
Toth
Linda A
LA
Ramkumar
Vickram
V
D000818:Animals; D001479:Basal Ganglia / Q000166:cytology / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002110:Caffeine / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D043682:Receptor, Adenosine A1 / Q000096:biosynthesis; D043705:Receptor, Adenosine A2A / Q000096:biosynthesis*; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D000697:Central Nervous System Stimulants; D044385:GTP-Binding Protein alpha Subunits; D052002:NF-kappa B p50 Subunit; D012333:RNA, Messenger; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2; D002110:Caffeine