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

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Received for publication June 28, 2006.
Revised August 16, 2006.
Accepted for publication August 18, 2006.

Voltage-dependent Block of NMDA Receptors by Dopamine D1 Receptor Ligands

Changhai Cui 1*, Ming Xu 2, Marco Atzori 3

1 Blanchette Rockefeller Neurosciences Institute 2 University of Chicago 3 University of Texas at Dallas

* Address correspondence to: E-mail: changhai{at}brni-jhu.org

Abstract

Abstract Accumulating evidence indicates that dopamine and D1 receptor ligands modulate NMDA receptors through a variety of D1 receptor-dependent mechanisms. Here, we reveal a distinct D1 receptor-independent mechanism by which NMDA receptors are modulated. Using the 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.


Key words: Dopamine, Glutamate, Ion channel regulation, G protein regulation


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