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The Journal of Neuroscience, February 4, 2004, 24(5):1149-1158; doi:10.1523/JNEUROSCI.3922-03.2004

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Cellular/Molecular
Regulation of Dopamine D1 Receptor Function by Physical Interaction with the NMDA Receptors

Lin Pei,¹ Frank J. S. Lee,¹ Anna Moszczynska,¹ Brian Vukusic,¹ and Fang Liu^1,2,3,4

¹Department of Neuroscience, Centre for Addiction and Mental Health, Clarke Division, Toronto, Ontario, M5T 1R8 Canada, and Departments of ²Physiology and ³Psychiatry and ⁴Institute of Medical Science, University of Toronto, Toronto, Ontario, M5T 1R8 Canada

Functional interactions between dopamine D1-like receptors and NMDA subtype glutamate receptors have been implicated in the maintenance of normal brain activity and neurological dysfunction. Although modulation of NMDA receptor functions by D1 receptor activation has been the subject of extensive investigation, little is known as to how the activation of NMDA receptors alters D1 function. Here we report that NMDA receptors regulate D1 receptor function via a direct protein–protein interaction mediated by the carboxyl tail regions of both receptors. In both cotransfected cells and cultured hippocampal neurons the activation of NMDA receptors increases the number of D1 receptors on the plasma membrane surface and enhances D1 receptor-mediated cAMP accumulation via a SNARE-dependent mechanism. Furthermore, overexpression of mini-genes encoding either NR1 or D1 carboxyl tail fragments disrupts the D1–NR1 direct protein–protein interaction and abolishes NMDA-induced changes in both D1 cell surface expression and D1-mediated cAMP accumulation. Our results demonstrate that the D1–NR1 physical interaction enables NMDA receptors to increase plasma membrane insertion of D1 receptors and provides a novel mechanism by which the activation of NMDA receptors upregulates D1 receptor function. Understanding the molecular mechanisms by which D1 and NMDA receptors functionally interact may provide insight toward elucidating the molecular neurobiological mechanisms involved in many neuropsychiatric illnesses, such as schizophrenia.

Key words: dopamine receptors; NMDA receptors; protein–protein interactions; cAMP accumulation; receptor trafficking; G-proteins

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Received Aug 23, 2003; revised December 5, 2003; accepted December 8, 2003.

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