Dopamine D1 receptors mediate CREB phosphorylation via phosphorylation of the NMDA receptor at Ser897-NR1.
Addictive drugs such as amphetamine and cocaine stimulate the dopaminergic system, activate dopamine receptors and induce gene expression throughout the striatum. The signal transduction pathway leading from dopamine receptor stimulation at the synapse to gene expression in the nucleus has not been fully elucidated. Here, we present evidence that D1 receptor stimulation leads to phosphorylation of the transcription factor Ca2+ and cyclic AMP response element binding protein (CREB) in the nucleus by means of NMDA receptor-mediated Ca2+ signaling. Stimulation of D1 receptors induces the phosphorylation of Ser897 on the NR1 subunit by protein kinase A (PKA). This phosphorylation event is crucial for D1 receptor-mediated CREB phosphorylation. Dopamine cannot induce CRE-mediated gene expression in neurons transfected with a phosphorylation-deficient NR1 construct. Moreover, stimulation of D1 receptors or increase in cyclic AMP levels leads to an increase in cytosolic Ca2+ in the presence of glutamate, but not in the absence of glutamate, indicating the ability of dopamine and cyclic AMP to facilitate NMDA channel activity. The recruitment of the NMDA receptor signal transduction pathway by D1 receptors may provide a general mechanism for gene regulation that is fundamental for mechanisms of drug addiction and long-term memory.
Dudman
Joshua T
JT
Laboratory of Neuroplacticity, McLean Hospital, Belmont, Massachusetts 02478, USA.
Eaton
Molly E
ME
Rajadhyaksha
Anjali
A
Macías
Wendy
W
Taher
Muffadal
M
Barczak
Amy
A
Kameyama
Kimihiko
K
Huganir
Richard
R
Konradi
Christine
C
D000818:Animals; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D018698:Glutamic Acid / Q000494:pharmacology; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D017362:Cyclic AMP Response Element-Binding Protein; C409466:NR1 NMDA receptor; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D017868:Cyclic AMP-Dependent Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium