Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(s)

Johnson, Michael P.; Barda, David A.; Britton, Thomas C.; Emkey, Renee; Hornback, William J.; Jagdmann, G. Erik; McKinzie, David L.; Nisenbaum, Eric S.; Tizzano, Joseph P.; Schoepp, Darryle D.

doi:10.1007/s00213-004-2099-9

Cited by 152 publications

(131 citation statements)

References 51 publications

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“…In addition, the mutations did not prevent the 7TM domain from activating G proteins. The positive allosteric modulator (PAM), LY487379, which binds to the 7TM (26,27), activated all mutants except the C500A mutant (Fig. 1C); this is in agreement with our previous reports that mGluR PAMs become full agonists when the 7TM is disconnected from the VFT (24,28).…”

Section: Resultssupporting

confidence: 92%

Interdomain movements in metabotropic glutamate receptor activation

Huang

Cao

Jiang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Many cell surface receptors are multimeric proteins, composed of several structural domains, some involved in ligand recognition, whereas others are responsible for signal transduction. In most cases, the mechanism of how ligand interaction in the extracellular domains leads to the activation of effector domains remains largely unknown. Here we examined how the extracellular ligand binding to the venus flytrap (VFT) domains of the dimeric metabotropic glutamate receptors activate the seven transmembrane (7TM) domains responsible for G protein activation. These two domains are interconnected by a cysteine-rich domain (CRD). We show that any of the four disulfide bridges of the CRD are required for the allosteric coupling between the VFT and the 7TM domains. More importantly, we show that a specific association of the two CRDs corresponds to the active state of the receptor. Indeed, a specific crosslinking of the CRDs with intersubunit disulfide bridges leads to fully constitutively active receptors, no longer activated by agonists nor by allosteric modulators. These data demonstrate that intersubunit movement at the level of the CRDs represents a key step in metabotropic glutamate receptor activation.transmembrane signaling | G protein-coupled receptor | allosteric modulation M ost cell surface receptors are multimeric complexes of which each subunit is produced through the association of different domains throughout evolution (1-5). The activation of such receptor complexes is a result of coordinated conformational changes or movement of these different domains. Although an increasing amount of 3D crystal structures are becoming available, there is still limited information available on the structural basis of interdomain communication.Class C G protein-coupled receptors (GPCRs) represent key examples of such receptor complexes (6, 7). These receptors are obligatory dimers, either homo-or heterodimers, made by the association of two domains over evolutionary time; an extracellular bilobate venus flytrap (VFT) domain associated with a G protein activating 7 transmembrane (7TM) domain (Fig. 1A) (8). The VFTs are evolved from certain types of bacterial periplasmic binding proteins, especially those of the leucine-isoleucinevaline binding protein family involved in the transport of amino acids, sugars, or ions. Not surprisingly, class C GPCRs are activated by amino acids, i.e., the receptors for the two major neurotransmitters, the eight metabotropic glutamate receptors (mGluRs), and the GABA B receptor; sugar (the sweet taste receptors); or ions [the calcium-sensing receptor (CaSR)]. Accordingly, class C GPCRs represent exciting new targets for drug development for both the pharmaceutical and food industries, as illustrated by the number of drugs targeting these receptors already on the market (the GABA B receptor agonist baclofen, umami compounds, and various sweeteners such as aspartame, and cinacalcet, a positive allosteric modulator of the CaSR), and those in clinical trials (9-11).The precise mechanisms of how...

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Section: Resultssupporting

confidence: 92%

Interdomain movements in metabotropic glutamate receptor activation

Huang

Cao

Jiang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…2B) from adult (2-to 3-mo-old) P and NP rats. Whereas application of 200 nM LY379268 produced a 40-60% decrease below baseline levels in both regions in NP rats, consistent with the synaptic depression previously observed in DG and striatum of Sprague-Dawley rats (20,21), we observed less than 10% depression in P rats, consistent with uncompensated loss of mGluR2 function.…”

Section: Significancesupporting

confidence: 91%

“…These receptors are primarily located presynaptically and function as auto-receptors. mGluR2 is thought to be the receptor primarily responsible (20) for the group II mGluR-mediated presynaptic depression of glutamatergic neurons projecting onto striatum (21). Using field potential recordings, we examined effects of the group II mGluR agonist LY379268 on the synaptically evoked field excitatory postsynaptic potential (fEPSP) or population spike (PS) in dentate gyrus (DG)/hippocampal ( Fig.…”

Section: Significancementioning

confidence: 99%

Loss of metabotropic glutamate receptor 2 escalates alcohol consumption

Zhou¹,

Karlsson

Liang³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

107

116

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Identification of genes influencing complex traits is hampered by genetic heterogeneity, the modest effect size of many alleles, and the likely involvement of rare and uncommon alleles. Etiologic complexity can be simplified in model organisms. By genomic sequencing, linkage analysis, and functional validation, we identified that genetic variation of Grm2, which encodes metabotropic glutamate receptor 2 (mGluR2), alters alcohol preference in animal models. Selectively bred alcohol-preferring (P) rats are homozygous for a Grm2 stop codon (Grm2 *407) that leads to largely uncompensated loss of mGluR2. mGluR2 receptor expression was absent, synaptic glutamate transmission was impaired, and expression of genes involved in synaptic function was altered. Grm2 *407 was linked to increased alcohol consumption and preference in F2 rats generated by intercrossing inbred P and nonpreferring rats. Pharmacologic blockade of mGluR2 escalated alcohol self-administration in Wistar rats, the parental strain of P and nonpreferring rats. The causal role of mGluR2 in altered alcohol preference was further supported by elevated alcohol consumption in Grm2 −/− mice. Together, these data point to mGluR2 as an origin of alcohol preference and a potential therapeutic target. gene identification | selectively bred linesA lcoholism is a moderately to highly heritable disease (1, 2).The search for genetic variation influencing this complex disorder has yielded limited success. In human populations, candidate gene analyses have established roles for polymorphisms of ADH1B and ALDH2, both enzymes involved in alcohol metabolism (3). Genome-wide association studies (4-7) have implicated several genomic regions. However, the genes and functional variants that account for the genetic association signals remain largely unknown. Complex behavioral disorders may be influenced by many different genes. Most functional alleles are rare or uncommon, also contributing to genetic heterogeneity that hampers locus identification in population samples. Individual variants influencing alcoholism are also likely to be probabilistic in their actions, with limited effect sizes on risk of the disease itself. All of these factors pose significant challenges for identification of genes and functional variants contributing to alcoholism by population-based analyses in people.Model organisms, including selectively bred lines (8-10), offer a potentially powerful framework for genomic analyses to identify genes and their functional variants that contribute to complex disorders. The selective breeding process reduces genetic heterogeneity and enriches to high frequency variants that influence the targeted phenotype. Alcohol-preferring (P) and nonpreferring (NP) rats, a seminal rat model of alcoholism, were bred from Wistar rats by 30-70 generations of bidirectional selection for alcohol preference. These rats model human alcoholism in several ways. They voluntarily consume excessive amounts of alcohol with sustained high blood alcohol concentrations, consume alcohol fo...

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“…At present, eight subtypes of mGlus receptors have been identified, which can be subdivided into three groups (group I: mGlu1,5;group II: mGlu2,3;group III: mGlu4,6,7,8) based on their molecular structure, intracellular transduction pathway, and pharmacological profile (Conn and Pin 1997;Schoepp et al 1999). Group II mGlu ligands seem to be drugs with a particular promising therapeutic potential in psychiatric disorders, including anxiety and depression (Johnson et al 2005;Palucha and Pilc 2007). Group II mGlus are widely expressed in the rodent forebrain, although the distribution of mGlu2 is more restricted than that of mGlu3 (Ferraguti and Shigemoto 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Activation of mGlu2 and mGlu3 by LY354740 elicits inhibitory responses and has frequently been reported to have anxiolytic-like properties in various anxiety-related tests, such as stressinduced hyperthermia and the elevated plus maze in wildtype (WT) mice (Helton et al 1998;Linden et al 2004;Linden et al 2005a;Monn et al 1997;Spooren et al 2002;Johnson et al 2005;Galici et al 2006). Interestingly, recent studies involving mice lacking mGlu2 or mGlu3 receptors revealed that stimulation of both of these subtypes is necessary to observe anxiolytic-like efficacy of LY354740, since this effect was abolished in both knockout strains (Linden et al 2005b).…”

Section: Introductionmentioning

confidence: 99%

Individual contribution of metabotropic glutamate receptor (mGlu) 2 and 3 to c-Fos expression pattern evoked by mGlu2/3 antagonism

et al. 2008

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Objectives and materials and methods The aims of the present study were (1) to determine the neuronal activation pattern elicited by the group II mGlu antagonist LY341495 and (2) to evaluate the contribution of each group II mGlu subtype by using wild-type (WT) and knockout (KO) mice lacking either mGlu2 or mGlu3. c-Fos expression was used as a marker of neuronal activation. Results and discussion In WT mice, LY341495 induced widespread c-Fos expression in 68 out of 92 brain areas, including limbic areas such as the amygdala, septum, prefrontal cortex, and hippocampus. LY341495-induced cFos response was markedly decreased in the medial part of the central amygdala (CeM) and lateral septum (LS) in mGlu3-KO mice, as well as in the lateral parabrachial nucleus (LPB) in both KO strains. In the majority of investigated areas, LY341495-induced c-Fos expression was similar in KO and WT mice. Analysis of the cellular and subcellular distribution of mGlu2 and mGlu3 revealed a prevailing presence of mGlu3-immunoreactivity in the CeM in glial processes and in postsynapstic neuronal elements, whereas only rare presynaptic axon terminals were found immunoreactive for mGlu2. Conclusion In conclusion, our data indicate that group II mGlu blockade increases neuronal activation in a variety of brain areas, including many stress-and anxiety-related areas. The activation of two key brain areas, the CeM and LS, is mediated via mGlu3, while activation in the LPB involves both subtypes. Moreover, in the majority of investigated areas, LY341495-mediated neuronal activation appears to require a complex cross talk between group II mGlu subtypes or the action of LY341495 on additional receptors.

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Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(s)

Abstract: Taken together, the data indicate mGlu2 receptor potentiators have a unique use-dependent effect on presynaptic glutamate release, and show efficacy in several mGlu2/3-sensitive animal models of psychiatric disorders.

Cited by 152 publications

References 51 publications

Interdomain movements in metabotropic glutamate receptor activation

Interdomain movements in metabotropic glutamate receptor activation

Loss of metabotropic glutamate receptor 2 escalates alcohol consumption

Individual contribution of metabotropic glutamate receptor (mGlu) 2 and 3 to c-Fos expression pattern evoked by mGlu2/3 antagonism

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