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

Abstract

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.

Neurotoxicity of HIV-1 Tat protein: Involvement of D1 dopamine receptor☆

“…Previous studies in different cell culture models have focused on the role of NMDA receptor-controlled pathways in the mechanism of Tat neurotoxicity (King et al, 2006;Perez et al, 2001;Wang et al, 1999;Magnuson et al, 1995). There is considerable evidence of functional interactions and cross-talk between NMDA subtype glutamate receptors and dopamine D1-like receptors (Pei et al, 2004;Lee and Liu, 2004;Wirkner et al, 2004). Physical protein-protein interactions also can occur between the NMDA-receptor subunit-1 (NR1) and C-terminal peptides of D1 receptors; suggesting intracellular associations of direct relevance to dopaminergic modulation of NMDA currents (Pei et al, 2004).…”

“…Dopamine-glutamate interactions have been shown in different brain regions. Numerous studies have demonstrated that NMDA receptor function may be regulated by dopamine D1-like receptors, composed of D1 and D5 like receptors (Cepeda and Levine, 1998;Lee and Liu, 2004;Lezcano and Bergson, 2002;Pei et al, 2004;Cepeda and Levine, 2006;Missale et al, 2006). However, it is not known whether D1 dopamine receptors are involved in neurotoxicity of HIV-1 proteins.…”

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

“…DARs can signal through mechanisms independent of the traditional, G protein mediated pathways (Beaulieu et al, 2005;Zou et al, 2005;Lee and Liu, 2004;Pei et al, 2004;Liu et al, 2000;Lefkowitz and Shenoy, 2005). To determine if the DA-induced increase in cAMP is due to Gi/o proteins ( Figure 2) and/or G protein independent cascades, we examined the effect of DA in the presence of PTX, which specifically blocks the activation and dissociation of all members of the Gi/o family, except Gz.…”

“…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).…”

Modelos fisiopatológicos de la esquizofrenia; de dopamina a glutamato, de glutamato a GABA

“…De este modo, anormalidades sutiles en el equilibrio GABA/Glutamato que en etapas pre-adolescentes provocaban síntomas cognitivos y emocionales de intensidad leve a moderada, bajo el influjo de los cambios asociados a la adolescencia, particularmente en la actividad dopaminérgica (69) , podrían llevar a la emergencia de estados hiperglutamatérgicos de intensidad aún mayor. En apoyo a esta hipótesis, una creciente literatura neurocientífica básica indica que la señal dopaminérgica ejerce un poderoso efecto potenciador de la neurotransmisión glutamatérgica a diversos niveles (70) . Así, dada la irreversibilidad de los reajustes sinápticos producidos en esta etapa del desarrollo, es esperable que, de no actuar a tiempo, la pérdida de conectividad producida por esta hiperactividad glutamatérgica alcance un nivel crítico que conduzca a estados de deterioro cognitivo y emocional sobre los cuales sea difícil intervenir una vez superado este período crítico.…”