Glutamatergic Receptors

The many subtypes of glutamatergic receptors in the CNS can be classified into two major subtypes: ionotropic and metabotropic receptors (see Figure 1-7).

Ionotropic glutamate receptors

The ionotropic glutamate receptor ion channels are assemblies of homo- or hetero-oligomeric subunits integrated into the neuron's membrane. Every channel is assembled of (most likely) four subunits associated into a dimer of dimers as has been observed in crystallographic studies (Ayalon and Stern-Bach 2001; Madden 2002). Every subunit consists of an extracellular amino-terminal and ligand binding domain, three transmembrane domains, a reentrant pore loop (located between the first and second transmembrane domains), and an intracellular carboxyl-terminal domain (Hollmann et al. 1994). The subunits associate through interactions between their amino-terminal domains, forming a dimer that undergoes a second dimerization mediated by interactions between the ligand binding domains and/or between transmembrane domains (Ayalon and Stern-Bach 2001; Madden 2002). Three different subgroups of glutamatergic ion channels have been identified on the basis of their pharmacological ability to bind different synthetic ligands, each of which is composed of a different set of subunits. The three subgroups are the NMDA receptors, the AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors, and the kainate receptor. The latter two groups are often referred to together as the "non-NMDA" receptors, but they undoubtedly subserve unique functions (see Figure 1-7). In the adult mammalian brain, NMDA and AMPA glutamatergic receptors are collocated in approximately 70% of the synapses (Bekkers and Stevens 1989). By contrast, at early stages of development, synapses are more likely to contain only NMDA receptors. Radioligand binding studies have shown that NMDA and AMPA receptors are found in high density in the cerebral cortex, hippocampus, striatum, septum, and amygdala.

NMDA receptors

The NMDA receptor is activated by glutamate and requires the presence of a co-agonist, namely glycine or D-serine, to be activated, a process that likely varies in importance according to brain region (Panatier et al. 2006). However, the binding of both glutamate and glycine is still not sufficient for the NMDA receptor channel to open, since at resting membrane potential, the NMDA ion channel is blocked by Mg2+ ions. Only when the membrane is depolarized (e.g., by the activation of AMPA or kainate receptors on the same postsynaptic neuron) is the Mg2+ blockade relieved. Under these conditions, the NMDA receptor channel will open and permit the entry of both Na+ and Ca2+ (see Figure 1-7).

The NMDA receptor channel is composed of a combination of NR1, NR2A, NR2B, NR2C, NR2D, NR3A, and NR3B subunits (see Figure 1-7). The binding site for glutamate has been localized to the NR2 subunit, and the site for the co-agonist glycine has been localized to the NR1 subunit, which is required for receptor function. Two molecules of glutamate and two of glycine are thought to be necessary to activate the ion channel. Within the ion channel, two other sites have been identified—the sigma (a) site and the phencyclidine (PCP) site. The hallucinogenic drug PCP, ketamine, and the experimental drug dizocilpine (MK-801) all bind at the latter site and are considered noncompetitive receptor antagonists that inhibit NMDA receptor channel function.

In clinical psychiatric studies, ketamine has been shown to transiently induce psychotic symptoms in schizophrenic patients and to produce antidepressant effects in some depressed patients (Krystal et al. 2002). Building on these preclinical and preliminary clinical data, recent clinical trials have investigated the clinical effects of glutamatergic agents in subjects with mood disorders. Recent clinical studies have demonstrated effective and rapid antidepressant action of glutamatergic agents, including ketamine, an NMDA receptor antagonist, and riluzole, a glutamate release inhibitor (Sanacora et al. 2007; Zarate et al. 2006a). These and other data have led to the hypothesis that alterations in neural plasticity in critical limbic and reward circuits, mediated by increasing the postsynaptic AMPA-to-NMDA throughput, may represent a convergent mechanism for antidepressant action (Zarate et al. 2006b). This line of research holds considerable promise for developing new treatments for depression and bipolar disorder. The NMDA receptor agonists glycine, D-serine, and D-cycloserine have been shown to improve cognition and decrease negative symptoms in patients with schizophrenia who are receiving antipsychotics (Coyle et al. 2002). NMDA receptors in the amygdala may also be of critical importance in the process of transforming a fixed and consolidated fear memory to a labile state (Ben Mamou et al. 2006).

NMDA receptors play a critical role in regulating synaptic plasticity (Malenka and Nicoll 1999). The best-studied forms of synaptic plasticity in the CNS are long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic transmission. The molecular mechanisms of LTP and LTD have been extensively characterized and have been proposed to represent cellular models of learning and memory (Malenka and Nicoll 1999). Induction of LTP and LTD in the CA1 region of the hippocampus and in many regions of the brain has now clearly been demonstrated to be dependent on NMDA receptor activation. During NMDA receptor-dependent synaptic plasticity, Ca2 + influx through NMDA receptors can activate a wide variety of kinases and/or phosphatases that in turn modulate synaptic strength. An important development was the finding that two of the primary molecules involved—CaMKII and the NMDA subtype of glutamate receptor—form a tight complex with each other at the synapse (Lisman and McIntyre 2001). Interestingly, this binding appears to enhance both the autophosphorylation of the kinase and the ability of the entire holoenzyme, which has 12 subunits, to become hyperphosphorylated (Lisman and McIntyre 2001). This hyperphosphorylated state has been postulated to represent a "memory switch" that can lead to long-term strengthening of the synapse by multiple mechanisms. One important mechanism involves direct phosphorylation of the glutamate-activated AMPA receptors, which increases their conductance. Furthermore, CaMKII, once bound to the NMDA receptor, may organize additional anchoring sites for AMPA receptors at the synapse. Switching of synaptic NMDA receptor subunits, which bind CaMKII, for other NMDA receptor subunits having no affinity for this enzyme dramatically reduces LTP, demonstrating that glutamate and calcium signaling interactions are critical for learning and memory (Barria and Malinow 2005).

While the NMDA receptor clearly plays important roles in plasticity, abundant evidence has shown that excessive glutamatergic signaling is also involved in neuronal toxicity. With anoxia or hypoglycemia, the highly energy-dependent uptake mechanisms that keep glutamate compartmentalized in presynaptic terminals fail. Within minutes, glutamate is massively released into the synaptic space, resulting in activation of excitatory amino acid receptors. This leads to depolarization of target neurons via AMPA and kainate receptors and then to inappropriate and excessive activation of NMDA receptors. Considerable data suggest that the large excess of Ca2+ entering cells via the NMDA receptor channel may represent an important step in the rapid cell death that occurs via excitotoxicity. AMPA receptors

The AMPA receptor is stimulated by the presence of glutamate and characteristically produces a fast excitatory synaptic signal that is responsible for the initial reaction to glutamate in the synapse. In fact, as discussed above, it is generally believed that it is the activation of the AMPA receptor that results in neuronal depolarization sufficient to liberate the Mg2+ cation from the NMDA receptor, thereby permitting its activation. The AMPA receptor channel is composed of the combination of the GluR1, GluR2, GluR3, and GluR4 subunits and requires two molecules of glutamate to be activated (see Figure 1-7). AMPA receptors have a lower affinity for glutamate than does the NMDA receptor, thereby allowing for more rapid dissociation of glutamate and, therefore, a rapid deactivation of the AMPA receptor (for a review, see Dingledine et al. 1999).

Studies have indicated that AMPA receptor subunits are direct substrates of protein kinases and phosphatases. Phosphorylation of the receptor subunits regulates not only the intrinsic channel properties of the receptor but also the interaction of the receptor with associated proteins that modulate the membrane trafficking and synaptic targeting of the receptors (discussed in Malinow and Malenka 2002). Additionally, protein phosphorylation of other synaptic proteins has been proposed to indirectly modulate AMPA receptor function by affecting the macromolecular complexes that are important for the presence of AMPA receptors at the synaptic plasma membrane (Malinow and Malenka 2002; Nestler et al. 2001). Studies have been elucidating the cellular mechanisms by which AMPA receptor subunit insertion and trafficking occur and have revealed two major mechanisms (Malinow and Malenka 2002; Nestler et al. 2001). The first mechanism is used for GluR1-containing AMPA receptor insertion and is regulated by activity. The second mechanism is governed by constitutive receptor recycling, mainly through GluR2/3 heteromers in response to activity-dependent signals. Data suggest that AMPA receptor subunit trafficking may play an important role in neuropsychiatric disorders. Thus, Nestler and associates have shown that the ability of drugs of abuse to elevate levels of the GluR1 subunit of AMPA glutamate receptors in the VTA of the midbrain is crucial for the development of sensitization (Carlezon and Nestler 2002). They have demonstrated that even transient increases in GluR1 levels within VTA neurons can trigger complex cascades of other molecular adaptations in these neurons and, within larger neural circuits, can cause enduring changes in the responses of the brain to drugs of abuse. Chronic lithium and valproate have been shown to reduce GluR1 expression in hippocampal synaptosomes, effects that may play a role in the delayed therapeutic effects of these agents (Du et al. 2003; Szabo et al. 2002).

Recent studies have sought to test the hypothesis that "antidepressant anticonvulsants," like traditional antidepressants, can enhance surface AMPA receptors (Du et al. 2007). It was found that the predominantly antidepressant anticonvulsants lamotrigine and riluzole significantly enhanced the surface expression of GluR1 and GluR2 in a time- and dose-dependent manner in cultured hippocampal neurons. By contrast, the predominantly antimanic anticonvulsant valproate significantly reduced surface expression of GluR1 and GluR2. Concomitant with the GluR1 and GluR2 changes, the peak value of depolarized membrane potential evoked by AMPA was significantly higher in lamotrigine- and riluzole-treated neurons, supporting the surface receptor changes. In addition, lamotrigine and riluzole, as well as the traditional antidepressant imipramine, increased GluR1 phosphorylation at GluR1 (S845) in the hippocampus after chronic in vivo treatment.

Recent clinical research has demonstrated a robust and rapid antidepressant effect of ketamine; studies were therefore undertaken to test the hypothesis that ketamine brings about its rapid antidepressant effect by enhancing AMPA relative to NMDA throughput (Maeng et al. 2008). Although the AMPA antagonist NBQX was without behavioral effects alone, it blocked the antidepressant-like effects of ketamine. AMPA antagonists also blocked ketamine-induced changes in hippocampal GluR1 AMPA receptor phosphorylation. Together, these results suggest that regulating AMPA relative to NMDA throughput in critical neuronal circuits may play an important role in antidepressant action.

Kainate receptors

The kainate receptor has pre- and postsynaptic roles, sharing some properties with AMPA receptors. It is composed of the combination of the GluR5, GluR6, GluR7, KA1, and KA2 subunits (see Figure 1-7). The precise role of kainate receptors in the mature CNS remains to be fully elucidated, although the activity of the receptors clearly plays a role in synaptic function in many brain areas. Increasing data suggest the involvement of aberrant synaptic plasticity in the pathophysiology of bipolar disorder. Kainate receptors contribute to synaptic plasticity in different brain regions involved in mood regulation, including the prefrontal cortex, hippocampus, and amygdala. GluR6 (GRIK2) is a subtype of kainate receptor whose chromosomal loci of 6q16.3-q21 have been identified as potentially harboring genetic polymorphism(s) contributing to an increased risk of mood disorders. The role of GluR6 in modulating animal behaviors correlated with mood symptoms was investigated using GluR6 knockout and wild-type mice (Shaltiel et al. 2008). GluR6 knockout mice appeared to attain normal growth and showed no neurological abnormalities. GluR6 mice showed increased basal- or amphetamine-induced activity, were extremely aggressive, took more risks, and consumed more saccharin (a measure of hedonic drive). Notably, most of these aberrant behaviors responded to chronic lithium administration. These results suggest that abnormalities in kainate receptor throughput generated by GluR6 gene disruption may lead to the concurrent appearance of a constellation of behaviors related to manic symptoms, including persistent hyperactivity; escalated irritability, aggression, and risk taking; and hyperhedonia.

Metabotropic glutamate receptors

The metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors. The eight types of receptors that currently have been cloned can be organized into three different subgroups (groups I, II, and III) based largely on the signaling transduction pathways that they activate (see Figure 1-7). These receptors have a large extracellular N-terminal consisting of two lobes forming a "venus flytrap" binding pocket involved in glutamate recognition and a cysteine-rich extracellular domain that connects with seven transmembrane domains separated by short intra- and extracellular loops (see Figure 1-7). The intracellular loop plays an important role in the coupling with and selectivity of the G protein. The cytoplasmic carboxyl-terminal domain is variable in length and is involved with G protein activation and coupling efficacy (Bruno et al. 2001; Conn and Pin 1997).

The mGluR group I includes the mGluRl (a, b, c, d), and mGluR5 (a, b) receptors (see Figure 1-7). They preferentially interact with the Gctq/n subunit of G proteins, leading to activation of the IP3/calcium and DAG/PKC cascades. The receptors are located on both pre- and postsynaptic neurons. Group II metabotropic receptors include mGluR2 and mGluR3, which have been best characterized as inhibiting adenylyl cyclase but, like many receptors coupled to Gi/Go, may also regulate ion channels. Group III receptors, which include mGluR4 (a, b), mGluR6, mGluR7 (a, b), and mGluR8 (a, b), are reported to produce inhibition of adenylyl cyclase as well, but also to interact with the phosphodiesterase enzyme regulating guanosine monophosphate (cGMP) levels (Cooper et al. 2001; Squire et al. 2003). The group II and III receptors are located in the presynaptic membrane and, because of their coupling with Gi/Go proteins, appear to negatively modulate glutamate and GABA neurotransmission output when activated (i.e., they serve as inhibitory auto- and heteroreceptors). Preclinical studies suggest that mGlu group II and III receptors are "extrasynaptic" in their localization; that is, they are located some distance from the synaptic cleft and are thus activated only under conditions of excessive (pathological?) glutamate release, when there is sufficient glutamate to diffuse out of the synapse to these receptors (Schoepp 2001). In preclinical studies, mGluR2/3 agonists have been demonstrated to exert anxiolytic, antipsychotic, and neuroprotective properties (Schoepp 2001).

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