Inhibition of the dopamine D1 receptor signaling by PSD-95.
Dopamine D1 receptors play an important role in movement, reward, and learning and are implicated in a number of neurological and psychiatric disorders. These receptors are concentrated in dendritic spines of neurons, including the spine head and the postsynaptic density. D1 within spines is thought to modulate the local channels and receptors to control the excitability and synaptic properties of spines. The molecular mechanisms mediating D1 trafficking, anchorage, and function in spines remain elusive. Here we show that the synaptic scaffolding protein PSD-95 thought to play a role in stabilizing glutamate receptors in the postsynaptic density, interacts with D1 and regulates its trafficking and function. Interestingly, the D1-PSD-95 interaction does not require the well characterized domains of PSD-95 but is mediated by the carboxyl-terminal tail of D1 and the NH(2) terminus of PSD-95, a region that is recognized only recently to participate in protein-protein interaction. Co-expression of PSD-95 with D1 in mammalian cells inhibits the D1-mediated cAMP accumulation without altering the total expression level or the agonist binding properties of the receptor. The diminished D1 signaling is mediated by reduced D1 expression at the cell surface as a consequence of an enhanced constitutive, dynamin-dependent endocytosis. In addition, genetically engineered mice lacking PSD-95 show a heightened behavioral response to either a D1 agonist or the psychostimulant amphetamine. These studies demonstrate a role for a glutamatergic scaffold in dopamine receptor signaling and trafficking and identify a new potential target for the modulation of abnormal dopaminergic function.
Zhang
Jingping
J
Department of Psychiatry, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts 01772, USA.
Vinuela
Angel
A
Neely
Mark H
MH
Hallett
Penelope J
PJ
Grant
Seth G N
SG
Miller
Gregory M
GM
Isacson
Ole
O
Caron
Marc G
MG
Yao
Wei-Dong
WD
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D015259:Dopamine Agents / Q000494:pharmacology; D034281:Dynamins / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects / Q000235:genetics; D015870:Gene Expression; D051528:Guanylate Kinases; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007858:Learning / Q000187:drug effects; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D001523:Mental Disorders / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D015259:Dopamine Agents; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D017447:Receptors, Dopamine D1; D017470:Receptors, Glutamate; D000661:Amphetamine; D000242:Cyclic AMP; D051528:Guanylate Kinases; D034281:Dynamins