R7BP complexes with RGS9-2 and RGS7 in the striatum differentially control motor learning and locomotor responses to cocaine.
In the striatum, signaling through G protein-coupled dopamine receptors mediates motor and reward behavior, and underlies the effects of addictive drugs. The extent of receptor responses is determined by RGS9-2/Gbeta5 complexes, a striatally enriched regulator that limits the lifetime of activated G proteins. Recent studies suggest that the function of RGS9-2/Gbeta5 is controlled by the association with an additional subunit, R7BP, making elucidation of its contribution to striatal signaling essential for understanding molecular mechanisms of behaviors mediated by the striatum. In this study, we report that elimination of R7BP in mice results in motor coordination deficits and greater locomotor response to morphine administration, consistent with the essential role of R7BP in maintaining RGS9-2 expression in the striatum. However, in contrast to previously reported observations with RGS9-2 knockouts, mice lacking R7BP do not show higher sensitivity to locomotor-stimulating effects of cocaine. Using a striatum-specific knockdown approach, we show that the sensitivity of motor stimulation to cocaine is instead dependent on RGS7, whose complex formation with R7BP is dictated by RGS9-2 expression. These results indicate that dopamine signaling in the striatum is controlled by concerted interplay between two RGS proteins, RGS7 and RGS9-2, which are balanced by a common subunit, R7BP.
Anderson
Garret R
GR
Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA.
Cao
Yan
Y
Davidson
Steve
S
Truong
Hai V
HV
Pravetoni
Marco
M
Thomas
Mark J
MJ
Wickman
Kevin
K
Giesler
Glenn J
GJ
Martemyanov
Kirill A
KA
D000818:Animals; D002478:Cells, Cultured; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D007858:Learning / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects* / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D020710:RGS Proteins / Q000172:deficiency / Q000378:metabolism*; D034622:RNA Interference / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D045442:Rotarod Performance Test / Q000379:methods; D018709:Statistics, Nonparametric; D014162:Transfection / Q000379:methods
D018765:Dopamine Uptake Inhibitors; C499440:R7BP protein, mouse; D020710:RGS Proteins; D034741:RNA, Small Interfering; C492038:Rgs7 protein, mouse; C116925:regulator of g-protein signaling 9; D003042:Cocaine