Potentiation of NMDA receptor currents by dopamine D1 receptors in prefrontal cortex - PubMed (original) (raw)

Potentiation of NMDA receptor currents by dopamine D1 receptors in prefrontal cortex

Guojun Chen et al. Proc Natl Acad Sci U S A. 2004.

Abstract

Interactions between dopamine and N-methyl-D-aspartate receptors (NMDARs) in prefrontal cortex (PFC) and other brain regions are believed to play an important role in normal mental function and neuropsychiatric disorders. In this study, we examined the regulation of NMDAR currents by the dopamine D1 receptor in PFC pyramidal neurons. Application of the D1 receptor agonist SKF81297 caused a prominent increase of the steady-state NMDA-evoked current in acutely isolated PFC pyramidal neurons. The D1 effect on NMDARs was independent of protein kinase A or protein phosphatase 1, but was abolished by incubation of neurons in Ca2+-free medium. Intracellular application of the Ca2+ chelator, calmodulin, or calmodulin inhibitors largely prevented the D1 modulation of NMDAR currents. Moreover, inhibiting PKC activity or disrupting PKC association with its anchoring protein also significantly reduced the D1 effect on NMDAR currents. This upregulation of NMDAR activity by dopamine D1 receptors and the previous finding on up-regulation of dopamine D1 receptors by NMDAR activation provide a cellular mechanism for the reciprocal interactions between D1 and NMDARs. These interactions may play an important role in modulating synaptic plasticity and thus in cognitive and emotional processes.

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Figures

Fig. 1.

Fig. 1.

Activation of D1 receptors reversibly enhanced NMDAR currents in acutely dissociated PFC pyramidal neurons. (A) Current traces taken from a representative neuron showing the effect of SKF81297 (10 μM) on NMDA (500 μM)-evoked currents. (B) Plot of the steady-state NMDAR current (_I_ss) as a function of time and agonist application. (C) Plot of _I_ss showing that the selective D1 antagonist SCH23390 (SCH) (10 μM) largely blocked the effect of SKF81297 (SKF).

Fig. 2.

Fig. 2.

The effect of SKF81297 (SKF) on NMDAR currents was independent of PKA/PP1. (A) Plot of _I_ss showing that dialysis with the PKA inhibitory peptide PKI6–22 (20 μM) did not prevent the SKF81297-induced potentiation of NMDAR currents. (B) Cumulative data (mean ± SE) showing the percentage control modulation of _I_ss by SKF81297 in the absence (n = 16) or presence of PKI6–22 (n = 15), or the membrane-permeable myristoylated PKA inhibitor PKI14–22 (0.2 μM, n = 10). (C) Plot of _I_ss showing that inhibiting PP1 activity with OA (0.1 μM) failed to affect the SKF81297-induced potentiation of NMDAR currents. (D) Cumulative data (mean ± SE) showing the percentage control modulation of _I_ss by SKF81297 in the absence (n = 34) or presence of OA (external application: 0.1 μM, n = 8; internal application: 1 μM, n = 23) or the PP1-anchoring inhibitory peptide Gm (20 μM, n = 20).

Fig. 3.

Fig. 3.

The effect of SKF81297 (SKF) on NMDAR currents depended on Ca2+. (A) Plot of _I_ss as a function of time and agonist application in neurons perfused in a Ca2+-free solution (10 μM EGTA added) or in the normal external solution (containing 1 mM Ca2+). (B) Representative current traces taken from the records used to construct A (at time points denoted by #). (Scale bars: 0.2 nA, 0.5 s.) (C) Plot of _I_ss as a function of time and agonist application in neurons dialyzed with the high BAPTA internal solution (10 mM) or the normal internal solution (containing 0.5 mM BAPTA). (D) Cumulative data (mean ± SE) showing the percentage control modulation of _I_ss by SKF81297 in normal conditions (n = 20), in the Ca2+-free solution (n = 7), or in neurons dialyzed with high BAPTA (n = 15). *, P <0.001, ANOVA.

Fig. 4.

Fig. 4.

The effect of SKF81297 (SKF) on NMDAR currents depended on CaM. (A) Plot of _I_ss as a function of time and agonist application in neurons loaded with or without CaM (10 μM). (B) Representative current traces taken from the records used to construct A (at time points denoted by #). (Scale bars: 0.2 nA, 0.5 s.) (C) Plot of _I_ss as a function of time and agonist application in neurons dialyzed with or without the CaM antagonist CDZ (20 μM). (D) Cumulative data (mean ± SE) showing the percentage control modulation of _I_ss by SKF81297 in normal conditions (n = 10) or in neurons dialyzed with CaM (n = 7), CDZ (n = 14) or the CaM inhibitory peptide MLCK peptide (MLCKP) (n = 12), or in the presence of the CaM-dependent protein kinase II inhibitor KN-93 (10 μM, n = 14) or the calcineurin inhibitor CsA (50 μM, n = 5). *, P <0.001, ANOVA.

Fig. 5.

Fig. 5.

The effect of SKF81297 (SKF) on NMDAR currents was attenuated by inhibiting PKC. (A) Plot of _I_ss as a function of time and agonist application in neurons loaded with or without the PKC inhibitory peptide PKC19–36 (4 μM). (B) Representative current traces taken from the records used to construct A (at time points denoted by #). (Scale bars: 0.2 nA, 0.5 s.) (C) Plot of _I_ss showing that the enhancing effect of SKF81297 was largely diminished in the presence of the PKC inhibitor bisindolylmaleimide (Bis, 1 μM). (D) Cumulative data (mean ± SE) showing the percentage control modulation of _I_ss by SKF81297 in normal conditions (n = 11) or in neurons dialyzed with PKC19–36 (n = 17), or in the presence of bisindolylmaleimide (Bis, n = 21). *, P <0.001, ANOVA.

Fig. 6.

Fig. 6.

The effect of SKF81297 (SKF) on NMDAR currents was reduced by disrupting the PKC/AKAP interaction but was not affected by inhibiting phospholipase C (PLC) or other signaling molecules. (A) Plot of _I_ss as a function of time and agonist application in neurons loaded with or without the peptide AKAP31–52 (40 μM). (B) Representative current traces taken from the records used to construct A (at time points denoted by #). (Scale bars: 0.2 nA, 0.5 s.) (C) Plot of _I_ss showing that the enhancing effect of SKF81297 was intact in the presence of the PLC inhibitor U73122 (1 μM). (D) Cumulative data (mean ± SE) showing the percentage control modulation of _I_ss by SKF81297 in normal conditions (n = 10) or in neurons dialyzed with AKAP31–52 (n = 15), or in the presence of U73122 (n = 4), the inositol-1-4-5-triphosphate receptor antagonist heparin (2 mg/ml, n = 4), the phosphoinositide 3-kinase inhibitor wortmannin (3 μM, n = 12), or the protein tyrosine kinase inhibitor genistein (100 μM, n = 16). *, P <0.001, ANOVA.

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