Adenosine A2A receptor signaling and golf assembly show a specific requirement for the gamma7 subtype in the striatum.
The adenosine A(2A) receptor (A(2A)R) is increasingly recognized as a novel therapeutic target in Parkinson disease. In striatopallidal neurons, the G-protein α(olf) subtype is required to couple this receptor to adenylyl cyclase activation. It is now well established that the βγ dimer also performs an active role in this signal transduction process. In principal, sixty distinct βγ dimers could arise from combinatorial association of the five known β and 12 γ subunit genes. However, key questions regarding which βγ subunit combinations exist and whether they perform specific signaling roles in the context of the organism remain to be answered. To explore these questions, we used a gene targeting approach to specifically ablate the G-protein γ(7) subtype. Revealing a potentially new signaling paradigm, we show that the level of the γ(7) protein controls the hierarchial assembly of a specific G-protein α(olf)β(2)γ(7) heterotrimer in the striatum. Providing a probable basis for the selectivity of receptor signaling, we further demonstrate that loss of this specific G-protein heterotrimer leads to reduced A(2A)R activation of adenylyl cyclase. Finally, substantiating an important role for this signaling pathway in pyschostimulant responsiveness, we show that mice lacking the G-protein γ(7) subtype exhibit an attenuated behavioral response to caffeine. Collectively, these results further support the A(2A)R G-protein α(olf)β(2)γ(7) interface as a possible therapeutic target for Parkinson disease.
Schwindinger
William F
WF
Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania 17822, USA.
Mihalcik
Lauren J Murphree
LJ
Giger
Kathryn E
KE
Betz
Kelly S
KS
Stauffer
Anna Maria
AM
Linden
Joel
J
Herve
Denis
D
Robishaw
Janet D
JD
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002110:Caffeine / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism*; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism; D044387:GTP-Binding Protein beta Subunits / Q000235:genetics / Q000378:metabolism; D044388:GTP-Binding Protein gamma Subunits / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D000697:Central Nervous System Stimulants; D044385:GTP-Binding Protein alpha Subunits; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D009097:Multienzyme Complexes; D043705:Receptor, Adenosine A2A; D002110:Caffeine