Structural, signalling and regulatory properties of the group I metabotropic glutamate receptors: prototypic family C G-protein-coupled receptors

HERMANS, Emmanuel; Challiss, R. A. J.

doi:10.1042/bj3590465

Cited by 277 publications

(239 citation statements)

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“…In many cases the negative signaling is due to a caspase-mediated cleavage of the receptor C-terminal domain (CTD) which either releases a pro-apoptotic C-terminal receptor fragment (Bordeaux et al, 2000;Llambi et al, 2001), or exposes a pro-apoptotic region that presumably remains bound to the cell membrane (Mehlen et al, 1998;Forcet et al, 2001;Thibert et al, 2003). While a specific cleavage of the mGlu1 CDT has not been described, it should be pointed out that a sequence analysis of the long CTD of the mGlu1a splice variant reveals six putative caspase cleavage sites, as well as multiple sequences that may potentially interact with a variety of intracellular proteins including: seven in absentia homolog-1A (Siah-1A) and calmodulin (Ishikawa et al, 1999;Kammermeier and Ikeda, 2001), G-proteincoupled receptor kinases (Dale et al, 2000), alpha-tubulin (Ciruela et al, 1999), tamalin/ cytohesin complex (Kitano et al, 2002), homer proteins (Brakeman et al, 1997;Tu et al, 1999), protein phosphatase 1C (Croci et al, 2003), protein kinase C, regulators of G-protein signaling (RGS) proteins, Src-family protein tyrosine kinase and arrestins (Valenti et al, 2002;Hermans and Challiss, 2001). Therefore, the mGlu1 CTD is well equipped to participate and interfere in various intracellular signaling processes.…”

Section: Discussionmentioning

confidence: 99%

Dual neurotoxic and neuroprotective role of metabotropic glutamate receptor 1 in conditions of trophic deprivation – Possible role as a dependence receptor

et al. 2008

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Group-I metabotropic glutamate receptors have been often implicated in various models of neuronal toxicity, however, the role played by the individual receptors and their putative mechanisms of action contributing to neurotoxicity or neuroprotection remain unclear. Here, using primary cultures of rat cerebellar granule cells and mouse cortical neurons, we show that conditions of trophic deprivation increased mGlu1 expression which correlated with the developing cell death. The inhibition of mGlu1 expression by specific siRNA attenuated toxicity, while adenovirus-mediated overexpression of mGlu1 resulted in increased cell death, indicating a causal relationship between the level of receptor expression and neuronal survival. In pharmacological experiments selective mGlu1 antagonists failed to protect from mGlu1-induced cell death, instead, neuronal survival was promoted by glutamate acting at mGlu1 receptors. Such properties are characteristic of a novel heterogeneous family of dependence receptors which control neuronal apoptosis. Our findings indicate that increased expression of mGlu1 in neurons creates a state of cellular dependence on the presence of its endogenous agonist glutamate. We propose a new role and a new mechanism for mGlu1 action. This receptor may play a crucial role in determining the fate of individual neurons during the development of the nervous system.

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Section: Discussionmentioning

confidence: 99%

Dual neurotoxic and neuroprotective role of metabotropic glutamate receptor 1 in conditions of trophic deprivation – Possible role as a dependence receptor

et al. 2008

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“…The fact that synaptic transmission at NMDA receptors is modulated by simultaneous activation of mGluR5 (Sorensen and Conn, 2003) could at least provide a clue for the effects of MPEP on the ADE. This functional coupling could result from the postsynaptic association of NMDA receptors with a complex of proteins, which includes different scaffolding proteins (eg PSD-95, Homer, Shank), but other receptors including mGluR5 are also linked to this complex (Kotecha et al, 2003), and activation of mGluR5 can lead to an enhancement of NMDA receptor function through phosphorylation by protein kinase C (Hermans and Challiss, 2001;Schoepp and Conn, 1993). The high affinity of MPEP for mGluR5 receptors, which is more than 1000-fold higher compared to NMDARs, makes it very unlikely that under the used conditions MPEP affects NMDARs directly (Oleary et al, 2000;Gubellini et al, 2001;Spooren et al, 2001;Kozela et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

mGluR5 Antagonist MPEP Reduces Ethanol-Seeking and Relapse Behavior

Bäckström

Bachteler

Koch

et al. 2003

Neuropsychopharmacol

235

178

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The glutamatergic system plays an important role in mediating neurobehavioral effects of ethanol. Metabotropic glutamate receptors subtype 5 (mGluR5) are modulators of glutamatergic neurotransmission and are abundant in brain regions known to be involved in ethanol self-administration. Here, we studied the effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a highly potent, noncompetitive mGlu5 receptor antagonist, on voluntary ethanol consumption and relapse behavior. For this purpose, we used two models for the measurement of relapse behavior: (i) reinstatement of ethanol-seeking behavior by drug-associated cues and (ii) the alcohol deprivation effect in long-term ethanol-consuming rats. In the first set of experiments, rats were trained to lever press for ethanol in the presence of a distinct set of cues. After extinction, the animals were exposed to the respective cues that initiated reinstatement of responding. A response-contingent ethanol prime further enhanced responding compared to the conditioned cues alone. Under these conditions, MPEP (0, 1, 3, and 10 mg/kg) attenuated ethanol seeking significantly and in a dose-related manner. However, at the highest dose, MPEP also decreased the number of inactive lever responses. In the second set of experiments, rats with 1 year of ethanol experience and repeated deprivation phases were used. A subchronic treatment with MPEP (twice daily; 0, 3, and 10 mg/kg) resulted in a significant and dose-dependent reduction of the alcohol deprivation effect (ADE). Although the same MPEP treatment regimen decreased baseline drinking, this effect was not as pronounced as on the ADE. These results show in two commonly used models of relapse to ethanol that pharmacological targeting of mGlu5 receptors may be a promising approach for the treatment of alcoholism.

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“…mGlu5 receptors directly interact with adenosine A 2A receptors (28) and potentiate adenosine A 2A -receptor signaling in an ERK-dependent manner in indirect pathway neurons (9). Furthermore, functions of mGlu1 and mGlu5 receptors are differentially regulated by PKC, G protein-coupled receptor kinase, regulator of G protein signaling, and Src-family protein tyrosine kinase (27,29). Signaling cascades, differentially activated by mGlu1 or mGlu5 receptors, might be factors in the selective regulation of DARPP-32 at Thr-34 and Thr-75.…”

Section: Regulation Of Darpp-32 Thr-34 Phosphorylation By Glutamate Nmentioning

confidence: 99%

“…The mechanisms of the selective regulation of Thr-34 and Thr-75 phosphorylation by mGlu5 and mGlu1 receptors, respectively, during the delayed phase are not clearly understood. Group I mGlu (mGlu1 and mGlu5) receptors preferentially activate a PLC signaling cascade but also are known to activate other signaling cascades (27). mGlu5 receptors directly interact with adenosine A 2A receptors (28) and potentiate adenosine A 2A -receptor signaling in an ERK-dependent manner in indirect pathway neurons (9).…”

Section: Regulation Of Darpp-32 Thr-34 Phosphorylation By Glutamate Nmentioning

confidence: 99%

Glutamate regulation of DARPP-32 phosphorylation in neostriatal neurons involves activation of multiple signaling cascades

Nishi

Watanabe²,

Higashi³

et al. 2005

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

120

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Dopamine-and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) plays a central role in medium spiny neurons in the neostriatum in the integration of various neurotransmitter signaling pathways. In its Thr-34-phosphorylated form, it acts as a potent protein phosphatase-1 inhibitor, and, in its Thr-75-phosphorylated form, it acts as a cAMP-dependent kinase inhibitor. Here, we investigated glutamate-dependent signaling cascades in mouse neostriatal slices by analyzing the phosphorylation of DARPP-32 at Thr-34 and Thr-75. Treatment with glutamate (5 mM) caused a complex change in DARPP-32 Thr-34 phosphorylation. An initial rapid increase in Thr-34 phosphorylation was NMDA͞␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)͞metabo-tropic glutamate-5 receptor-dependent and was mediated through activation of a neuronal nitric oxide synthase͞nitric oxide͞cGMP͞ cGMP-dependent kinase signaling cascade. A subsequent decrease in phosphorylation was attributable to activation of an NMDA͞ AMPA receptor͞Ca 2؉ ͞protein phosphatase-2B signaling cascade. This decrease was followed by rephosphorylation via a pathway involving metabotropic glutamate-5 receptor͞phospholipase C and extracellular receptor kinase signaling cascade. Treatment with glutamate initially decreased Thr-75 phosphorylation through activation of NMDA͞AMPA receptor͞Ca 2؉ ͞protein phosphatase-2A signaling. Thereafter, glutamate slowly increased Thr-75 phosphorylation through activation of metabotropic glutamate-1 receptor͞phospholipase C signaling. Our analysis of DARPP-32 phosphorylation in the neostriatum revealed that glutamate activates at least five different signaling cascades with different time dependencies, resulting in complex regulation of protein kinase and protein phosphatase activities.dopamine ͉ striatum ͉ nitric oxide ͉ metabotropic glutamate receptor ͉ protein phosphatase D ARPP-32, a dopamine-and cAMP-regulated phosphoprotein of 32 kDa, is a signal transduction molecule that is selectively enriched in medium spiny neurons in the neostriatum (1). Mice lacking DARPP-32 exhibit profound deficits in their molecular, electrophysiological, and behavioral responses to dopamine, drugs of abuse, and antipsychotic medication (2), indicating an essential role for DARPP-32 in dopamine signaling. DARPP-32 is phosphorylated at Thr-34 by cAMP-dependent protein kinase (PKA), resulting in its conversion into a potent inhibitor of protein phosphatase-1 (PP-1). DARPP-32 is phosphorylated at Thr-75 by cyclin-dependent kinase 5 (Cdk5) (3). DARPP-32 phosphorylated at Thr-75 inhibits PKA activity and thereby reduces the efficacy of dopamine signaling. Dopamine, by means of dopamine D1 receptors, activates PKA, which directly stimulates DARPP-32 Thr-34 phosphorylation and indirectly stimulates DARPP-32 Thr-75 dephosphorylation (4, 5). By regulating the activity of PKA and PP-1, dopamine controls the state of phosphorylation of various intracellular targets.Glutamate is the major excitatory neurotransmitter in the brain. The excitation of medium spiny neurons i...

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Structural, signalling and regulatory properties of the group I metabotropic glutamate receptors: prototypic family C G-protein-coupled receptors

Cited by 277 publications

References 0 publications

Dual neurotoxic and neuroprotective role of metabotropic glutamate receptor 1 in conditions of trophic deprivation – Possible role as a dependence receptor

Dual neurotoxic and neuroprotective role of metabotropic glutamate receptor 1 in conditions of trophic deprivation – Possible role as a dependence receptor

mGluR5 Antagonist MPEP Reduces Ethanol-Seeking and Relapse Behavior

Glutamate regulation of DARPP-32 phosphorylation in neostriatal neurons involves activation of multiple signaling cascades

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