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Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA
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(Received 13 October 2003;
accepted after revision 25 November 2003;
first published online 28 November 2003)
Corresponding author Z. Yan: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA. Email: zhenyan{at}buffalo.edu
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Introduction |
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The ionotropic glutamate receptors are classified as AMPA receptors, kainate receptors and NMDA receptors, based on their physiological and pharmacological properties. Each of these ligand-gated channels is an oligomeric complex composed of different subunits (Seeburg, 1993; Hollmann & Heinemann, 1994). Hypofunction of NMDA receptors has been implicated in schizophrenia (Tsai & Coyle, 2002). Administration of the non-competitive NMDA receptor antagonists, such as phencyclidine (PCP), produces behavioural symptoms that remarkably resemble schizophrenia in humans and animals, and exacerbates symptoms in schizophrenics (Javitt & Zukin, 1991; Jentsch & Roth, 1999).
The metabotropic glutamate receptors (mGluRs) are classified into three groups based on structural homology, signal transduction mechanisms and pharmacological properties (Nakanishi, 1992). These receptors modulate glutamatergic neurotransmission in an anatomically and functionally distinct manner (Schoepp & Conn, 1993; Conn & Pin, 1997), and thus provide important pharmacotherapeutic targets for psychiatric disorders associated with glutamatergic abnormalities. The group II family of mGluRs, which consists of mGluR2 and mGluR3, is primarily expressed in forebrain regions including PFC (Ohishi et al. 1993a,b; Petralia et al. 1996). It has been found that systemic administration of an mGluR2/3 agonist reverses behavioural impairments in the phencyclidine model of schizophrenia (Moghaddam & Adams, 1998). However, cellular mechanisms underlying the antipsychotic action of mGluR2/3 receptors remain unclear. The mGluR2/3-mediated presynaptic depression of evoked glutamate release (Baskys & Malenka, 1991; Lovinger & McCool, 1995; Cartmell & Schoepp, 2000) is thought to be one possible mechanism for the normalization of glutamatergic disruptions by group II mGluRs (Moghaddam & Adams, 1998). We sought to examine the postsynaptic interactions between mGluR2/3 and NMDA receptors in PFC neurones, which could also be important for the reversal of NMDAR hypofunction by group II mGluRs in the schizophrenia model.
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Methods |
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PFC neurones from young adult (3–5 weeks postnatal) rats (Sprague Dowley) or mice (CS7 BL6) were acutely dissociated using procedures similar to those previously described (Yan & Surmeier, 1997; Feng et al. 2001). All experiments were carried out with the approval of State University of New York at Buffalo Animal Care Committee. In brief, rats were anaesthetized by inhaling 2-bromo-2-chloro-1,1,1-trifluoroethane (1 ml (100 g)-1, Sigma) and decapitated; brains were quickly removed, iced and then blocked for slicing. The blocked tissue was cut in 400 µm slices with a Vibratome while bathed in a low Ca2+ (100 µM), Hepes-buffered salt solution (mM: 140 sodium isethionate, 2 KCl, 4 MgCl2, 0.1 CaCl2, 23 glucose, 15 Hepes, 1 kynurenic acid, pH 7.4, 300–305 mosmol l-1). Slices were then incubated for 1–6 h at room temperature (20–22°C) in a NaHCO3-buffered saline bubbled with 95% O2, 5% CO2 (mM): 126 NaCl, 2.5 KCl, 2 CaCl2, 2 MgCl2, 26 NaHCO3, 1.25 NaH2PO4, 10 glucose, 1 pyruvic acid, 0.05 glutathione, 0.1 NG-nitro-Loarginine, 1 kynurenic acid, pH 7.4, 300–305 mosmol l-1). All reagents were obtained from Sigma Chemical Co. (St Louis, MO, USA).
Slices were then removed into the low Ca2+ buffer and regions of the PFC were dissected and placed in an oxygenated Cell-Stir chamber (Wheaton, Inc., Millville, NJ, USA) containing papain (0.4 mg ml-1, Sigma) in Hepes-buffered Hanks' balanced salt solution (HBSS, Sigma) at 35°C. After 20–40 min of enzyme digestion, tissue was rinsed three times in the low Ca2+, Hepes-buffered saline and mechanically dissociated with a graded series of fire-polished Pasteur pipettes. The cell suspension was then plated into a 35 mm Lux Petri dish, which was then placed on the stage of a Nikon inverted microscope.
Whole-cell recordings
Whole-cell recordings of currents in dissociated or cultured neurones employed standard voltage-clamp techniques (Yan et al. 1999; Wang et al. 2003). The internal solution consisted of (mM): 180 N-methyl-D-glucamine (NMG), 40 Hepes, 4 MgCl2, 0.1 BAPTA, 12 phosphocreatine, 2 Na2ATP, 0.2 Na3GTP, 0.1 leupeptin, pH 7.2–7.3, 265–270 mosmol l-1. The external solution consisted of (mM): 127 NaCl, 20 CsCl, 10 Hepes, 1 CaCl2, 5 BaCl2, 12 glucose, 0.001 TTX, 0.02 glycine, pH 7.3–7.4, 300–305 mosmol l-1. Recordings were obtained with an Axon Instruments 200B patch clamp amplifier that was controlled and monitored with an IBM PC running pCLAMP (v. 8) with a DigiData 1320 series interface (Axon instruments, Union City, CA, USA). Electrode resistances were typically 2–4 M
in the bath. After seal rupture, series resistance (4–10 M) was compensated (70–90%). Care was exercised to monitor the constancy of the series resistance, and recordings were terminated whenever a significant increase (> 20%) occurred. The cell membrane potential was held at -60 mV. NMDA (100 µM) was applied for 2 s every 30 s. About 30 min of recordings were performed on individual cells for most experiments. Cells with unstable NMDA responses (>20% decline throughout the recording) were discarded. Drugs were applied with a gravity-fed ‘sewer pipe’ system. The array of application capillaries (ca 150 µm i.d.) was positioned a few hundred micrometres from the cell under study. Solution changes were effected by the SF-77B fast-step solution stimulus delivery device (Warner Instrument Co., Hamden, CT, USA).
The mGluR ligands (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC), 2S-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]3-(xanth-9-yl) propanoic acid (LY341495), (RS)-1-amino-5-phosphonoindan-1-carboxylic acid (APICA), 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) and 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) were from Tocris (Ballwin, MO, USA). The second messenger reagents staurosporine, bisindolylmaleimide, cpt-cAMP, myristoylated PKI[14–22], U73122, 2-aminoethoxydiphenylborane (2APB), genistein, 3-(4-chlorophenyl)1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (PP2), roscovitine, KN-93 and cyclosporin A were from Calbiochem (San Diego, CA, USA). They were made up as concentrated stocks and stored at -20°C. The final DMSO concentration in all applied solutions was less than 0.1%. Stocks were thawed and diluted immediately prior to use.
Data analyses were performed with AxoGraph (Axon Instruments), Kaleidagraph (Albeck Software, Reading, PA, USA) and StatView (Abacus Concepts, Inc.). For analysis of statistical significance, Mann–Whitney U tests were performed to compare the current amplitudes in the presence or absence of agonists. ANOVA was performed to compare the differential degrees of current modulation between groups subjected to different treatment.
Western blot analysis
For detecting activated PKC, a phospho-PKC (pan) antibody that recognizes PKC
, ßI, ßII, 
, 
, and 
isoforms only when phosphorylated at a carboxy-terminal residue homologous to Ser660 of PKCßII was used in the Western blot analysis. PFC slices were prepared as previously described (Gu et al. 2003). Equal amounts of protein from slice homogenates were separated on 7.5% polyacrylamide gels and transferred to nitrocellulose membranes. The blots were blocked with 5% non-fat dry milk for 1 h at room temperature. Then the blots were incubated with the phospho-PKC (pan) antibody (Cell Signalling 1: 2000) for 1 h at room temperature. After being rinsed, the blots were incubated with horseradish peroxidase-conjugated antirabbit antibodies (Amersham, 1: 2000) for 1 h at room temperature. Following three washes, the blots were exposed to the enhanced chemiluminescence substrate. Then the blots were stripped for 1 h at 50°C followed by saturation in 5% non-fat dry milk and incubated with a PKC antibody (Santa Cruz 1: 2000) recognizing the , ß, 
isoforms for the detection of the total PKC. For detecting NMDA receptors that are phosphorylated by PKC, a phospho-S896.NR1 antibody (Upstate, 1: 1000) was used. Quantification was obtained from densitometric measurements of immunoreactive bands on films. Data correspond to the mean ±S.D. of 3–8 samples per condition, and were analysed by ANOVA.
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Results |
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To test the potential impact of group II mGluR receptors on NMDAR functions, we examined the effect of APDC, a potent and highly selective mGluR2/3 receptor agonist (Schoepp et al. 1999), on NMDA receptor-mediated currents in acutely isolated PFC pyramidal neurones. The glutamatergic PFC pyramidal neurones were readily distinguished from GABAergic interneurones by their distinct morphological features: a pyramidal-shaped soma and a prominent apical dendrite (Feng et al. 2001; Cai et al. 2002). Application of NMDA evoked a partially desensitizing inward current that was blocked by the NMDA receptor antagonist D-APV (50 µM) or MK-801 (10 µM) (Fig. 1A and B), confirming mediation by the NMDA receptor. Application of APDC (50 µM) caused a potent enhancement in the amplitude of NMDAR currents in isolated PFC pyramidal neurones. The time course and current traces from a representative cell is shown in Fig. 1C and D). The APDC-induced increase of NMDAR currents was reversible and had fast onset kinetics. Following recovery from the first application, a second application of APDC resulted in a similar response (94.3 ± 3.4% of first response, n= 18). As summarized in Fig. 1E, APDC (50 µM) significantly (P < 0.01, Mann–Whitney) enhanced the amplitude of currents evoked by different concentrations of NMDA (100 µM: 19.2 ± 0.6%, n= 87; 50 µM: 10.3 ± 2.0%, n= 4; 500 µM: 22.5 ± 2.4%, n= 3; 1000 µM: 27.7 ± 2.3%, n= 3). In contrast, APDC had little effect on AMPAR currents in dissociated PFC pyramidal neurones (Figs 1F (2.1 ± 2.1%, n= 5, P > 0.05, Mann–Whitney). In cultured PFC pyramidal neurones (2–3 weeks in vitro), APDC also caused a potentiation of NMDA (100 µM)-evoked currents (14.2 ± 0.8%, n= 34, P < 0.01, Mann–Whitney, data not shown), consistent with the results obtained from acutely isolated neurones.
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The opening of NMDAR channels is regulated by the voltage-sensitive Mg2+ block; we therefore examined whether the mGluR2/3 modulation of NMDAR currents was through changing the Mg2+ block in a voltage-dependent mechanism. Membrane potentials were held at different levels, and NMDAR currents were recorded in Mg2+-containing versus Mg2+-free solutions. As shown in Fig. 3A and B, APDC produced similar enhancement of NMDAR currents irrespective of the holding potentials (-70, -40 and -20 mV) in the cell perfused with an Mg2+-free solution. Moreover, the APDC effect on NMDAR currents was similar irrespective of the extracellular Mg2+ concentrations (0 mM, 2 mM) in the cell voltage-clamped at -40 mV. The percentage control modulation of NMDAR currents by APDC at different membrane potentials and different concentrations of Mg2+ is summarized in Fig. 3C. The lack of changes of the APDC effect suggests that mGluR2/3 receptors potentiate NMDAR currents through a mechanism independent of membrane voltages or Mg2+ block.
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Involvement of PKC in the mGluR2/3 potentiation of NMDAR currents
We next examined the mechanisms mediating the potentiation of NMDAR currents by group II mGluR receptors. A classical signal transduction pathway for mGluR2/3 receptors is to couple to Gi/o-type G proteins to inhibit adenylate cyclase and cAMP formation (Conn & Pin, 1997). While PKA phosphorylation of NMDAR subunits changes the channel activity (Raman et al. 1996; Tingley et al. 1997; Westphal et al. 1999), we found that the mGluR2/3 enhancement of NMDAR currents was unlikely through the inhibition of PKA. As shown in Fig. 4A, application of the membrane-permeant PKA activator cpt-cAMP (50 µM) failed to block APDC-induced increase of NMDAR currents. Dialysis with the PKA inhibitory peptide PKI[5–24] (20 µM) also failed to prevent APDC from potentiating NMDAR currents (n= 5, data not shown).
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If mGluR2/3 receptors were exerting their effect through PKC, then inhibiting the activation of PKC should eliminate the effect of APDC on NMDAR currents. As shown in Fig. 4B, the broad-spectrum kinase inhibitor staurosporine (1 µM), which has a high affinity to PKC, largely blocked the APDC-induced enhancement of NMDAR currents. A more specific PKC inhibitor, bisindolylmaleimide (Bisl, 1 µM), with high selectivity for PKC, ß, , and isozymes (Toullec et al. 1991), also eliminated the APDC effect, and washing off the PKC inhibitor led to recovery of APDC enhancement of NMDAR currents (Fig. 4C,D). Since conventional PKC isoforms (PKC, ß, ) depend on Ca2+ for their activation (Tanaka & Nishizuka 1994), we dialysed neurones with a high concentration (10 mM) of BAPTA, a potent and rapid Ca2+ chelator, and examined APDC modulation of NMDAR currents under this condition. As shown in Fig. 4E, high BAPTA significantly attenuated the effect of APDC on NMDAR currents.
The ability of various inhibitors to block the APDC effect on NMDAR currents, expressed as a percentage of the modulation in the absence of these reagents, is summarized in Fig. 4F. APDC had a significantly (P < 0.005, ANOVA) smaller effect on NMDAR currents in the presence of staurosporine (30.7 ± 6.8% of control modulation, n= 13). Similarly, the effect of APDC on NMDAR currents in the presence of bisindolylmaleimide was significantly (P < 0.005, ANOVA) smaller (26.2 ± 7.9% of control modulation, n= 14). Dialysis with high BAPTA also significantly (P < 0.005, ANOVA) attenuated the APDC potentiation of NMDAR currents (38.7 ± 4.0% of control modulation, n= 13). However, the effect of APDC was not affected by cpt-cAMP (98.3 ± 10.3% of control modulation, n= 10) or the membrane-permeant PKA inhibitor, myristoylated PKI[14–22] (81.8 ± 6.4% of control modulation, n= 9). Taken together, these data suggest that mGluR2/3 receptor-mediated potentiation of NMDAR currents is through a mechanism dependent on PKC activation.
Since activation of PKC is often triggered by the phospholipid cascade, we then tested whether the phospholipid pathway is involved in the mGluR2/3 regulation of NMDA receptors. Application of the phospholipase C (PLC) inhibitor U73122 (4 µM) had little effect on basal NMDAR currents. However, in the presence of U73122, APDC significantly lost the ability to potentiate NMDAR currents in half of the neurones we tested (n= 12/24). A representative example is shown in Fig. 5A and B. In the other 12 neurones, U73122 failed to alter the APDC enhancement of NMDAR currents (data not shown). To examine the involvement of intracellular Ca2+ stores, the membrane-permeant IP3 receptor antagonist 2APB (15 µM) was applied. In many of the neurones we tested (n= 10/17), 2APB caused an increase in NMDAR currents, whereas in others (n= 7/17), 2APB had little effect on basal NMDAR currents. The enhancing effect of APDC was markedly diminished by 2APB in most cases (n= 12/17). A representative example is shown in Fig. 5C. In the other five neurones, 2APB failed to affect the APDC enhancement of NMDAR currents (data not shown). As summarized in Fig. 5D, in a subset of PFC pyramidal neurones, inhibiting PLC with U73122 significantly (P < 0.01, ANOVA) attenuated the APDC enhancement of NMDAR currents (25.1 ± 6.4% of control modulation, n= 12 out of 24 neurones), whereas blocking Ca2+ release from intracellular Ca2+ stores via IP3 receptors prevented APDC from increasing NMDAR currents (16.4 ± 5.5% of control modulation, n= 12 out of 17 neurones). Thus, these results suggest that the phospholipid pathway is involved in the mGluR2/3 regulation of NMDAR currents in a subset of PFC pyramidal neurones. In other neurones, mGluR2/3 receptors may activate PKC through an unknown mechanism to enhance NMDAR currents.
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Given the PKC dependence of mGluR2/3 enhancement of NMDAR currents, we would like to know whether it is through a direct action of PKC (Tingley et al. 1997; Lan et al. 2001) or indirectly via a PKC downstream signalling molecule. Two possible candidates that can be activated by PKC and can directly regulate NMDARs are the tyrosine kinase Src (Lu et al. 1999) and the cyclin-dependent kinase 5 (cdk5, Li et al. 2001; Liu et al. 2001). Thus, we tested the role of these kinases in mGluR2/3 regulation of NMDAR currents.
As shown in Fig. 6A, bath application of the broad-spectrum tyrosine kinase inhibitor genistein (50 µM) did not affect the ability of APDC to enhance NMDAR currents. The specific Src kinase inhibitor PP2 (20 µM) also failed to block the APDC-induced increase of NMDAR currents (n= 4, data not shown). Similarly, suppressing cdk5 activity with the specific inhibitor roscovitine (50 µM, Hellmich et al. 1992) was without effect on the APDC potentiation of NMDAR currents (Fig. 6B and C). Furthermore, in mutant mice with targeted deletion of the neuronal specific activator of cdk5, p35 (Tsai et al. 1994; Chae et al. 1997), APDC caused similar enhancement of NMDAR currents as in wild-type mice (p35-/-: 19.5 ± 2.0%, n= 8; WT: 22.8 ± 2.6%, n= 10).
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The mGluR2/3-induced increase in PKC activity and PKC phosphoylation of NMDA receptors in PFC slices
Since the electrophysiological data suggest that the APDC-induced potentiation of NMDAR currents is likely to be through a direct activation of PKC, we then examined whether activation of mGluR2/3 receptors can indeed increase PKC activity. Because the catalytic competence of many PKC isozymes depends on autophosphorylation at the carboxyl terminus on a conserved residue (Behn-Krappa & Newton, 1999), a phospho-specific pan PKC antibody that detects PKC isoforms only when phosphorylated at this residue was used to detect activated PKC. As shown in Fig. 7A, application of APDC (50 µM, 10 min) to cortical slices induced a marked increase in the activated PKC. This effect of APDC was not altered by antagonizing mGluR1/5 receptors with MPEP (5 µM) and CPCCOEt (50 µM), but was blocked by the mGluR2/3 antagonist LY341495 (1 µM). The levels of total PKC were not changed by any of these treatments. Quantification data (Fig. 7B) exhibited a 3.2 ± 0.9-fold increase of PKC activity by APDC treatment (n= 8), which was abolished by LY341495 (1.2 ± 0.3-fold, n= 4), but not by MPEP and CPCCOEt (3.0 ± 0.6-fold, n= 4). These results suggest that activation of mGluR2/3 receptors elevates the kinase activity of PKC in PFC neurones.
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Discussion |
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The NMDAR channel activity can be regulated by protein phosphorylation/dephosphorylation via a variety of protein kinases/phosphatases (Lieberman & Mody, 1994; Lu et al. 1999; Westphal et al. 1999). Different groups of mGluRs, by coupling to distinct second-messenger cascades, can regulate NMDAR channels in a complex manner. Activation of group I mGluRs in cortical neurones induced an enhancement of NMDAR currents through the Pyk2/Src-family kinase pathway (Heidinger et al. 2002). In this study, we found that group II mGluRs enhanced NMDAR currents in PFC pyramidal neurones via a mechanism dependent on PKC activation. Biochemical data also confirmed that mGluR2/3 receptors elevated the level of activated PKC in PFC slices. These data suggest that postsynaptic group II mGluRs in PFC neurones may link to the phospholipid cascade, instead of coupling to the classical inhibition of PKA pathway, to regulate NMDA receptors. Consistent with this, it has been found that postsynaptic group II mGluRs induced long-term depression in PFC through the PLC/PKC/Ca2+-dependent mechanism (Otani et al. 2002). Moreover, agonists for group II mGluRs are found to potentiate the action of group I mGluRs on phosphoinositide turnover (Schoepp et al. 1996; Mistry et al. 1998) and postsynaptic Ca2+ augmentation (Cho et al. 2000). Interestingly, a recent study has found that the therapeutically effective antipsychotic drug clozapine augments NMDA-induced responses through a mechanism involving PKC activation in PFC pyramidal neurones (Jardemark et al. 2003). It supports our speculation that the group II mGluR/PKC-mediated facilitation of NMDAR currents may underlie the antipsychotic action of mGluR2/3 agonists (Moghaddam & Adams, 1998).
A previous study (Otani et al. 2002) demonstrated that group II mGluR agonists decrease synaptically evoked NMDAR-EPSPs, which is not surprising given the prominent role of group II mGluRs in presynaptic depression (Marek et al. 2000; Cartmell & Schoepp, 2000). With the opposite pre- and postsynaptic effects of group II mGluR activation on NMDAR responses, the net effect of group II mGluRs on NMDAR functions in vivo could be complicated. We hypothesize that in response to mGluR2/3 activation, the decreased glutamate release will prevent the activation of extrasynaptic NMDA receptors and reduce the number of synaptic NMDA receptors that are activated. Meanwhile, the activated synaptic NMDA receptors will have higher sensitivity or conductance due to the postsynaptic modification of channel properties. The net consequence could be a preferential facilitation of subsets of synaptic NMDA receptors and suppression of other synaptic and extrasynaptic NMDA receptors, which could lead to a higher ‘signal-to-noise’ ratio of the NMDA signalling at some synaptic sites.
Several mechanisms have been proposed to account for the PKC-mediated up-regulation of NMDAR channels. One mechanism for PKC to potentiate the NMDA response is to increase the probability of channel openings and reduce the voltage-dependent Mg2+ block of NMDAR channels (Chen & Huang, 1992). Alternatively, PKC enhances NMDA-evoked currents through activation of the non-receptor tyrosine kinase (Src) signalling cascade (Lu et al. 1999). Our data ruled out these two possibilities, suggesting that the group II mGluR/PKC regulation of NMDAR channels is through a mechanism independent of Mg2+ block or Src, as well as other signalling molecules including cdk5, CaMKII and calcineurin. Thus, mGluR2/3 may alter the biophysical properties of NMDAR channels through direct PKC phosphorylation of NR1 subunit (Tingley et al. 1993). Biochemical evidence has shown that PKC phosphorylation of NR1 decreases its affinity for calmodulin (Hisatsune et al. 1997). Hence, mGluR2/3 activation of PKC could potentiate NMDAR currents by preventing calmodulin from binding to the NR1 subunit and thereby inhibiting the inactivation of NMDARs by Ca2+/calmodulin (Ehlers et al. 1996; Zhang et al. 1998). The possible involvement of this mechanism is confirmed by our results showing the blockade of APDC effects with a high concentration of Ca2+ chelator. Another mechanism that may underlie the mGluR2/3 potentiation of NMDAR currents involves the PKC-induced rapid delivery of functional NMDARs to the surface of dendrites and spines through regulated exocytosis (Lan et al. 2001). The exact mechanism for the mGluR2/3-PKC regulation of NMDAR channels awaits to be further examined.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Baskys A & Malenka RC (1991). Agonists at metabotropic glutamate receptors presynaptically inhibit EPSCs in neonatal rat hippocampus. J Physiol 444, 687–701.
Behn-Krappa A & Newton AC (1999). The hydrophobic phosphorylation motif of conventional protein kinase C is regulated by autophosphorylation. Curr Biol 9, 728–737.[CrossRef][Medline]
Cai X, Gu Z, Zhong P, Ren Y & Yan Z (2002). Serotonin 5-HT1A receptors regulate AMPA receptor channels through inhibiting CaMKII in prefrontal cortical pyramidal neurons. J Biol Chem 277, 36553–36562.
Carlsson A, Waters N, Holm-Waters S, Tedroff J, Nilsson M & Carlsson ML (2001). Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Annu Rev Pharmacol Toxicol 41, 237–260.[CrossRef][Medline]
Carr DB & Sesack SR (1996). Hippocampal afferents to the rat prefrontal cortex: synaptic targets and relation to dopamine terminals. J Comp Neurol 369, 1–15.[CrossRef][Medline]
Cartmell J & Schoepp DD (2000). Regulation of neurotransmitter release by metabotropic glutamate receptors. J Neurochem 75, 889–907.[CrossRef][Medline]
Chae T, Kwon YT, Bronson R, Dikkes P, Li E & Tsai LH (1997). Mice lacking p35, a neuronal specific activator of cdk5, display cortical lamination defects, seizures, and adult lethality. Neuron 18, 29–42.[CrossRef][Medline]
Chen L & Huang LY (1992). Protein kinase C reduces Mg2+ block of NMDA-receptor channels as a mechanism of modulation. Nature 356, 521–523.[CrossRef][Medline]
Cho K, Kemp N, Noel J, Aggleton JP, Brown MW & Bashir ZI (2000). A new form of long-term depression in the perirhinal cortex. Nat Neurosci 3, 150–156.[CrossRef][Medline]
Conde F, Marie-Lepoivre E, Audinat E & Crepel F (1995). Afferent connections of the medial frontal cortex of the rat. II. Cortical and subcortical afferents. J Comp Neurol 352, 567–593.[CrossRef][Medline]
Conn PJ & Pin JP (1997). Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37, 205–237.[CrossRef][Medline]
Cull-Candy S, Brickley S & Farrant M (2001). NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol 11, 327–335.[CrossRef][Medline]
Davis KI, Kahn Rs, Ko G & Davidson M (1991). Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 148, 1474–1486.
Ehlers MD, Zhang S, Bernhardt JP & Huganir RL (1996). Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 subunit. Cell 84, 745–755.[CrossRef][Medline]
Feng J, Cai X, Zhao JH & Yan Z (2001). Serotonin receptors modulate GABAA receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons. J Neurosci 21, 6502–6511.
Goldman-Rakic PS (1995). Cellular basis of working memory. Neuron 14, 477–485.[CrossRef][Medline]
Gu Z, Zhong P & Yan Z (2003). Activation of muscarinic receptors inhibits ß-amyloid peptide-induced signaling in cortical slices. J Biol Chem 278, 17546–17556.
Heidinger V, Manzerra P, Wang XQ, Strasser U, Yu SP, Choi DW & Behrens MM (2002). Metabotropic glutamate receptor 1-induced upregulation of NMDA receptor current: mediation through the Pyk2/Src-family kinase pathway in cortical neurons. J Neurosci 22, 5452–5461.
Hellmich MR, Pant HC, Wada E & Battey JF (1992). Neuronal cdc2-like kinase: a cdc2-related protein kinase with predominantly neuronal expression. Proc Natl Acad Sci U S A 89, 10867–10871.
Hisatsune C, Umemori H, Inoue T, Michikawa T, Kohda K & Mikoshiba K & Yamamoto T (1997). Phosphorylation-dependent regulation of N-methyl-D-aspartate receptors by calmodulin. J Biol Chem 272, 20805–20810.
Hollmann M & Heinemann S (1994). Cloned glutamate receptors. Annu Rev Neurosci 17, 31–108.[CrossRef][Medline]
Jardemark KE, Ninan I, Liang X & Wang RY (2003). Protein kinase C is involved in clozapine's facilitation of N-methyl-D-aspartate- and electrically evoked responses in pyramidal cells of the medial prefrontal cortex. Neuroscience 118, 501–512.[CrossRef][Medline]
Javitt DC & Zukin SR (1991). Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148, 1301–1308.
Jentsch JD & Roth RH (1999). The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20, 201–225.[CrossRef][Medline]
Kingston AE, Ornstein PL, Wright RA, Johnson BG, Mayne NG, Burnett JP, Belagaje R, Wu S & Schoepp DD (1998). LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors. Neuropharmacology 37, 1–12.[CrossRef][Medline]
Klein J, Iovino M, Vakil M, Shinozaki H & Loffelholz K (1997). Ontogenetic and pharmacological studies on metabotropic glutamate receptors coupled to phospholipase D activation. Neuropharmacology 36, 305–311.[CrossRef][Medline]
Lan JY, Skeberdis VA, Jover T, Grooms SY, Lin Y, Araneda RC, Zheng X & Bennett MV & Zukin RS (2001). Protein kinase C modulates NMDA receptor trafficking and gating. Nat Neurosci 4, 382–390.[CrossRef][Medline]
Lewis DA & Lieberman JA (2000). Catching up on schizophrenia: Natural history and neurobiology. Neuron 28, 325–334.[CrossRef][Medline]
Li BS, Sun MK, Zhang L, Takahashi S, Ma W, Vinade L, Kulkarni AB, Brady RO & Pant HC (2001). Regulation of NMDA receptors by cyclin-dependent kinase-5. Proc Natl Acad Sci U S A 98, 12742–12747.
Lieberman DN & Mody I (1994). Regulation of NMDA channel function by endogenous Ca2+-dependent phosphatase. Nature 369, 235–239.[CrossRef][Medline]
Liu F, Ma XH, Ule J, Bibb JA, Nishi A, Demaggio AJ, Yan Z, Nairn AC & Greengard P (2001). Regulation of cyclin-dependent kinase 5 and casein kinase 1 by metabotropic glutamate receptors. Proc Natl Acad Sci U S A 98, 11062–11068.
Lovinger DM & Mccool BA (1995). Metabotropic glutamate receptor-mediated presynaptic depression at corticostriatal synapses involves mGluR2 or 3. J Neurophysiol 73, 1076–1083.
Lu WY, Xiong ZG, Lei S, Orser BA, Dudek E, Browning MD & Macdonald JF (1999). G-protein-coupled receptors act via protein kinase C and Src to regulate NMDA receptors. Nat Neurosci 2, 331–338.[CrossRef][Medline]
Marek GJ, Wright RA, Schoepp DD, Monn JA & Aghajanian GK (2000). Physiological antagonism between 5-hydroxytryptamine (2A) and group II metabotropic glutamate receptors in prefrontal cortex. J Pharmacol Exp Ther 292, 76–87.
Miller EK (1999). The prefrontal cortex: complex neural properties for complex behavior. Neuron 22, 15–17.[CrossRef][Medline]
Mistry R, Golding N & Challiss RA (1998). Regulation of phosphoinositide turnover in neonatal rat cerebral cortex by group I- and II-selective metabotropic glutamate receptor agonists. Br J Pharmacol 123, 581–589.[CrossRef][Medline]
Moghaddam B & Adams BW (1998). Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281, 1349–1352.
Monyer H, Burnashev N, Laurie DJ, Sakmann B & Seeburg PH (1994). Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12, 529–540.[CrossRef][Medline]
Nakanishi S (1992). Molecular diversity of glutamate receptors and implications for brain function. Science 258, 597–603.
Ohishi H, Shigemoto R, Nakanishi S & Mizuno N (1993a). Distribution of the messenger RNA for a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat. Neuroscience 53, 1009–1018.[CrossRef][Medline]
Ohishi H, Shigemoto R, Nakanishi S & Mizuno N (1993b). Distribution of the mRNA for a metabotropic glutamate receptor (mGluR3) in the rat brain: an in situ hybridization study. J Comp Neurol 335, 252–266.[CrossRef][Medline]
Omkumar RV, Kiely MJ, Rosenstein AJ, Min KT & Kennedy MB (1996). Identification of a phosphorylation site for calcium/calmodulin dependent protein kinase II in the NR2B subunit of the N-methyl-D-aspartate receptor. J Biol Chem 271, 31670–31678.
Otani S, Daniel H, Takita M & Crepel F (2002). Long-term depression induced by postsynaptic group II metabotropic glutamate receptors linked to phospholipase C and intracellular calcium rises in rat prefrontal cortex. J Neurosci 22, 3434–3444.
Petralia RS, Wang YX, Niedzielski AS & Wenthold RJ (1996). The metabotropic glutamate receptors, mGluR2 and mGluR3, show unique postsynaptic, presynaptic and glial localizations. Neuroscience 71, 949–976.[CrossRef][Medline]
Raman IM & Tong G & Jahr CE (1996). Beta-adrenergic regulation of synaptic NMDA receptors by cAMP-dependent protein kinase. Neuron 16, 415–421.[CrossRef][Medline]
Schoepp DD & Conn PJ (1993). Metabotropic glutamate receptors in brain function and pathology. Trends Pharmacol Sci 14, 13–20.[Medline]
Schoepp DD & Jane DE & Monn JA (1999). Pharmacological agents acting at subtypes of metabotropic glutamate receptors. Neuropharmacology 38, 1431–1476.[CrossRef][Medline]
Schoepp DD & Marek GJ (2002). Preclinical pharmacology of mGluR2/3 receptor agonists: novel agents for schizophrenia? Current Drug Targets – CNS Neurol Disorders 1, 215–225.[CrossRef]
Schoepp DD, Salhoff CR, Wright RA, Johnson BG, Burnett JP, Mayne NG, Belagaje R, Wu S & Monn JA (1996). The novel metabotropic glutamate receptor agonist 2R,4R-APDC potentiates stimulation of phosphoinositide hydrolysis in the rat hippocampus by 3,5-dihydroxyphenylglycine: evidence for a synergistic interaction between group 1 and group 2 receptors. Neuropharmacology 35, 1661–1672.[CrossRef][Medline]
Seeburg PH (1993). The TINS/TIPS lecture: the molecular biology of mammalian glutamate recptor channels. Trends Neurosci 16, 359–365.[CrossRef][Medline]
Strack S & Colbran RJ (1998). Autophosphorylation-dependent targeting of calcium/calmodulin-dependent protein kinase II by the NR2B subunit of the N-methyl-D-aspartate receptor. J Biol Chem 273, 20689–20692.
Tanaka C & Nishizuka Y (1994). The protein kinase C family for neuronal signaling. Annu Rev Neurosci 17, 551–567.[CrossRef][Medline]
Tingley WG, Ehlers MD, Kameyama K, Doherty C, Ptak JB, Riley CT & Huganir RL (1997). Characterization of protein kinase A and protein kinase C phosphorylation of the N-methyl-D-aspartate receptor NR1 subunit using phosphorylation site-specific antibodies. J Biol Chem 272, 5157–5166.
Tingley WG, Roche KW, Thompson AK & Huganir RL (1993). Regulation of NMDA receptor phosphorylation by alternative splicing of the C-terminal domain. Nature 364, 70–73.[CrossRef][Medline]
Toullec D, Pianetti P, Coste H, Bellevergue P, Grand-perret T, Ajakane M, Baudet V, Boissin P, Boursier E, Loriolle F et al. (1991). The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. J Biol Chem 266, 15771–15781.
Tsai G & Coyle JT (2002). Glutamatergic mechanisms in schizophrenia. Annu Rev Pharm Toxicol 42, 165–179.[CrossRef][Medline]
Tsai LH, Delalle I, Caviness VS Jr, Chae T & Harlow E (1994). p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature 371, 419–423.[CrossRef][Medline]
Vicini S, Wang JF, Li JH, Zhu WJ, Wang YH, Luo JH, Wolfe BB & Grayson DR (1998). Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors. J Neurophysiol 79, 555–566.
Wang X, Zhong P, Gu Z & Yan Z (2003). Regulation of NMDA receptors by dopamine D4 signaling in prefrontal cortex. J Neurosci 23, 9852–9861.
Westphal RS, Tavalin SJ, Lin JW, Alto NM, Fraser ID, Langeberg LK, Sheng M & Scott JD (1999). Regulation of NMDA receptors by an associated phosphatase-kinase signaling complex. Science 285, 93–96.
Williams K (1993). Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. Mol Pharmacol 44, 851–859.[Abstract]
Wittmann M, Marino MJ & Conn PJ (2002). Dopamine modulates the function of group II and group III metabotropic glutamate receptors in the substantia nigra pars reticulata. J Pharmacol Exp Ther 302, 433–441.
Yan Z, Hsieh-Wilson L, Feng J, Tomizawa K, Allen PB, Fienberg AA, Nairn AC & Greengard P (1999). Protein phosphatase 1 modulation of neostriatal AMPA channels: regulation by DARPP-32 and spinophilin. Nat Neurosci 2, 13–17.[CrossRef][Medline]
Yan Z & Surmeier DJ (1997). D5 dopamine receptors enhance Zn2+-sensitive GABAA currents in striatal cholinergic interneurons through a PKA/PP1 cascade. Neuron 19, 1115–1126.[CrossRef][Medline]
Zhang S, Ehlers MD, Bernhardt JP, Su CT & Huganir RL (1998). Calmodulin mediates calcium-dependent inactivation of N-methyl-D-aspartate receptors. Neuron 21, 443–453.[CrossRef][Medline]
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