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First published on August 18, 2006; DOI: 10.1124/mol.106.028332

0026-895X/06/7005-1761-1770$20.00
Mol Pharmacol 70:1761-1770, 2006

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Voltage-Dependent Block of N-Methyl-D-aspartate Receptors by Dopamine D1 Receptor Ligands

Changhai Cui, Ming Xu, and Marco Atzori

Blanchette Rockefeller Neurosciences Institute, Rockville, Maryland (C.C.); Department of Anesthesia and Critical Care, University of Chicago, Chicago, Illinois (M.X.); and School of Behavior and Brain Sciences, University of Texas at Dallas, Texas (M.A.)

Accumulating evidence indicates that dopamine and D1 receptor ligands modulate N-methyl D-aspartate (NMDA) receptors through a variety of D1 receptor-dependent mechanisms. In this study, we reveal a distinct D1 receptor-independent mechanism by which NMDA receptors are modulated. Using the human embryonic kidney (HEK) cell recombinant system and dissociated neurons, we have discovered that dopamine and several D1 ligands act as voltage-dependent, open-channel blockers for NMDA receptors, regardless of whether they are agonists or antagonists for D1 receptors. Analysis of structural and functional relationships of D1 ligands revealed the elements that are critical for their binding to NMDA receptors. Furthermore, using D1 receptor knockout mice, we verified that this channel-blocking effect was independent of D1 receptors. Finally, we demonstrated that D1 ligands functionally interact with Mg2+ block through multiple sites, implying a possible role of the direct channel block under physiological conditions. Our results suggest that the direct inhibition of NMDA receptors by dopamine D1 receptor ligands is due to the channel pore block rather than receptor-receptor interactions.

Received June 27, 2006; accepted August 18, 2006

Address correspondence to: Changhai Cui, Blanchette Rockefeller Neurosciences Institute, A and R Building, 3rd Floor, 9601 Medical Center Drive, Rockville, MD 20850. E-mail: changhai{at}brni-jhu.org




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