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

Abstract

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 SNAREdependent 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.

Dendritic distributions of dopamine D1 receptors in the rat nucleus accumbens are synergistically affected by startle-evoking auditory stimulation and apomorphine

“…Important clues are provided by our study in the basolateral amygdala, where we show that application of dopamine significantly decreases glutamate NMDA receptor-mediated postsynaptic currents through postsynaptic mechanisms, which may include co-trafficking of D1R and NMDA receptor . This is suggested by known protein-protein interactions between the C-terminals of D1R and the NR1 subunit of NMDA receptor (Lee et al, 2002;Fiorentini et al, 2003;Pei et al, 2004;Pickel et al, 2006). Dopaminergic and glutamatergic terminals converge on the same dendritic spine in the Acb (Sesack and Pickel, 1990;Pinto et al, 2003), where NMDA receptor antagonists also disrupt sensorimotor gating (Mansbach and Geyer, 1989;Bakshi et al, 1999).…”

“…Auditory stimulation (AS), such as that used in acoustic startle testing, transiently decreases extracellular dopamine in the Acb (Humby et al, 1996). Moreover, glutamate activation of NMDA receptors that are coexpressed with D1R in many Acb dendrites, can increase D1R plasma membrane insertion, as well as recruitment of D1Rs to dendritic spines (Scott et al, 2002;Pei et al, 2004;Hara and Pickel, 2005). Thus, either apomorphine binding to D1/D2 receptors or AS resulting in decreased dopamine and/or altered activation of glutamatergic inputs to Acb may affect the expression of D1Rs in selective neuronal compartments within the Acb shell and core neurons.…”

Arthropod D2 receptors positively couple with cAMP through the Gi/o protein family

“…Fourth, GPCRs are known to interact directly with target proteins. For example, DARs can physically interact with, and activate ionotropic glutamate receptors (Zou et al, 2005;Lee and Liu, 2004;Pei et al, 2004;Liu et al, 2000). Fifth, GPCRs can activate additional cascades, like the mitogen activated protein kinase (MAPK) cascade via crosstalk (Werry et al, 2005).…”

Dopaminergic signaling in dendritic spines

“…However, in the presence of NR2B, the NR1-D1 receptor complex was translocated to the plasma membrane, suggesting that D1 and NMDARs were assembled within intracellular compartments as constitutive heteromeric complexes [41]. In both heterologous cells and cultured neurons, activation of NMDARs recruited D1 receptors to the plasma membrane via a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-dependent mechanism, resulting in enhancement of D1-mediated cAMP accumulation [84]. These studies, while not entirely consistent mechanistically, all appear to support direct D1-NMDAR interaction.…”