Direct interactions between NMDA and D1 receptors: a tale of tails

Considerable evidence has accumulated describing a complex interaction between the dopaminergic and glutamatergic pathways. Efforts to describe the mechanisms underlying this complex interaction have implicated a functional interaction between dopamine and glutamate receptors. Classically, the interaction between D(1) and NMDA (N-methyl-D-aspartate) receptors has been proposed to involve the activation of second-messenger signalling cascades after receptor stimulation. However, in recent years, another paradigm has emerged which involves the direct interaction between D(1) and NMDA receptors. The physical association between D(1) and NMDA receptors is unique in that two different regions of the D(1) C-terminus are able to couple specifically and physically with two different NMDA subunits. The selective modulation of multiple NMDA receptor-mediated functions by direct interactions with D(1) receptors may form a new avenue to identify specific targets for therapeutics to modulate NMDA receptor-governed synaptic plasticity, neuronal development and disease states.