Modulation of D2R-NR2B interactions in response to cocaine.
Dopamine-glutamate interactions in the neostriatum determine psychostimulant action, but the underlying molecular mechanisms remain elusive. Here we found that dopamine stimulation by cocaine enhances a heteroreceptor complex formation between dopamine D2 receptors (D2R) and NMDA receptor NR2B subunits in the neostriatum in vivo. The D2R-NR2B interaction is direct and occurs in the confined postsynaptic density microdomain of excitatory synapses. The enhanced D2R-NR2B interaction disrupts the association of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) with NR2B, reduces NR2B phosphorylation at a CaMKII-sensitive site (Ser1303), and inhibits NMDA receptor-mediated currents in medium-sized striatal neurons. Furthermore, the regulated D2R-NR2B interaction is critical for constructing behavioral responsiveness to cocaine. Our findings here uncover a direct and dynamic D2R-NR2B interaction in striatal neurons in vivo. This type of dopamine-glutamate integration at the receptor level may be responsible for synergistically inhibiting the D2R-mediated circuits in the basal ganglia and fulfilling the stimulative effect of psychostimulants.
Liu
Xian-Yu
XY
Department of Basic Medical Science, University of Missouri-Kansas City, School of Medicine, Kansas City, Missouri 64108, USA.
Chu
Xiang-Ping
XP
Mao
Li-Min
LM
Wang
Min
M
Lan
Hong-Xiang
HX
Li
Ming-Hua
MH
Zhang
Guo-Chi
GC
Parelkar
Nikhil K
NK
Fibuch
Eugene E
EE
Haines
Michelle
M
Neve
Kim A
KA
Liu
Fang
F
Xiong
Zhi-Gang
ZG
Wang
John Q
JQ
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003001:Cloning, Molecular; D003042:Cocaine / Q000494:pharmacology*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004594:Electrophysiology; D018698:Glutamic Acid / Q000502:physiology; D047468:Immunoprecipitation; D008124:Locomotion / Q000502:physiology; D008297:Male; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*
D000697:Central Nervous System Stimulants; D018076:DNA, Complementary; D018765:Dopamine Uptake Inhibitors; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D003042:Cocaine