title: Impaired D2 dopamine receptor function in mice lacking type 5 adenylyl cyclase.
abstract: Dopamine receptor subtypes D1 and D2, and many other seven-transmembrane receptors including adenosine receptor A2A, are colocalized in striatum of brain. These receptors stimulate or inhibit adenylyl cyclases (ACs) to produce distinct physiological and pharmacological responses and interact with each other synergistically or antagonistically at various levels. The identity of the AC isoform that is coupled to each of these receptors, however, remains unknown. To investigate the in vivo role of the type 5 adenylyl cyclase (AC5), which is preferentially expressed in striatum, mice deficient for the AC5 gene were generated. The genetic ablation of the AC5 gene eliminated >80% of forskolin-induced AC activity and 85-90% of AC activity stimulated by either D1 or A2A receptor agonists in striatum. However, D1- or A2A-specific pharmaco-behaviors were basically preserved, whereas the signal cascade from D2 to AC was completely abolished in AC5(-/-), and motor activity of AC5(-/-) was not suppressed by treatment of cataleptic doses of the antipsychotic drugs haloperidol and sulpiride. Interestingly, both haloperidol and clozapine at low doses remarkably increased the locomotion of AC5(-/-) in the open field test that was produced in part by a common mechanism that involved the increased activation of D1 dopamine receptors. Together, these results suggest that AC5 is the principal AC integrating signals from multiple receptors including D1, D2, and A2A in striatum and the cascade involving AC5 among diverse D2 signaling pathways is essential for neuroleptic effects of antipsychotic drugs.
authors.affiliation: Department of Neuroscience and Ewha Institute of Neuroscience, Ewha Womans University School of Medicine, Seoul, 110-783, Korea.
authors.forename: Ko-Woon
authors.initials: KW
authors.lastname: Lee
authors.forename: Jang-Hee
authors.initials: JH
authors.lastname: Hong
authors.forename: In Young
authors.initials: IY
authors.lastname: Choi
authors.forename: Yongzhe
authors.initials: Y
authors.lastname: Che
authors.forename: Ja-Kyeong
authors.initials: JK
authors.lastname: Lee
authors.forename: Sung-Don
authors.initials: SD
authors.lastname: Yang
authors.forename: Chang-Woo
authors.initials: CW
authors.lastname: Song
authors.forename: Ho Sung
authors.initials: HS
authors.lastname: Kang
authors.forename: Jae-Heun
authors.initials: JH
authors.lastname: Lee
authors.forename: Jai Sung
authors.initials: JS
authors.lastname: Noh
authors.forename: Hee-Sup
authors.initials: HS
authors.lastname: Shin
authors.forename: Pyung-Lim
authors.initials: PL
authors.lastname: Han
mesh_terms: D000262:Adenylyl Cyclases / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP; D018491:Dopamine Agonists / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology; D005328:Fetal Viability / Q000235:genetics; D018390:Gene Targeting; D006579:Heterozygote; D006720:Homozygote; D007527:Isoenzymes / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D043705:Receptor, Adenosine A2A; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D020536:Enzyme Activators; D007527:Isoenzymes; D043705:Receptor, Adenosine A2A; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D018047:Receptors, Purinergic P1; D005576:Colforsin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V