1 These authors contributed equally to this paper.
Dopamine D1 receptors mediate CREB phosphorylation via phosphorylation of the NMDA receptor at Ser897–NR1
Article first published online: 4 FEB 2004
Journal of Neurochemistry
Volume 87, Issue 4, pages 922–934, November 2003
How to Cite
Dudman, J. T., Eaton, M. E., Rajadhyaksha, A., Macías, W., Taher, M., Barczak, A., Kameyama, K., Huganir, R. and Konradi, C. (2003), Dopamine D1 receptors mediate CREB phosphorylation via phosphorylation of the NMDA receptor at Ser897–NR1. Journal of Neurochemistry, 87: 922–934. doi: 10.1046/j.1471-4159.2003.02067.x
- Issue published online: 4 FEB 2004
- Article first published online: 4 FEB 2004
- Received June 6, 2003; revised manuscript received August 1, 2003; accepted August 4, 2003.
- calcium/calmodulin kinase;
- cyclic AMP;
- dopamine D1 receptor;
- protein kinase A
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.