Synergy between l-DOPA and a novel positive allosteric modulator of metabotropic glutamate receptor 4: Implications for Parkinson's disease treatment and dyskinesia

Bennouar, Khaled-Ezaheir; Uberti, Michelle A.; Melon, Christophe; Bacolod, Maria D.; Jimenez, Hermogenes N.; Cajina, Manuel; Goff, Lydia Kerkerian‐Le; Doller, Darı́o; Gubellini, Paolo

doi:10.1016/j.neuropharm.2012.03.022

Cited by 87 publications

(102 citation statements)

References 62 publications

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“…The detection of mGlu 2/4 interactions in dorsal striatum is consistent with electrophysiology data that both mGlu 2 and mGlu 4 act presynaptically to reduce excitatory transmission at corticostriatal synapses Bennouar et al, 2013), although mGlu 2 and mGlu 4 may also colocalize on other striatal axon terminals. Similarly, medial prefrontal cortex samples contain many axon terminals where mGlu 2 and mGlu 4 might colocalize.…”

Section: Discussionsupporting

confidence: 87%

“…In addition to striatopallidal and STN-SNc synapses, immunohistochemistry studies revealed that mGlu 4 is expressed at corticostriatal synapses, which represent the primary input to the basal ganglia from the motor cortex (Corti et al, 2002). Consistent with expression studies, Bennouar et al (2013) recently reported that the mGlu 4 PAM Lu AF21934 reduces corticostriatal transmission. To further understand the role of mGlu 4 in regulation of basal ganglia function, we evaluated the ability of PHCCC to reduce corticostriatal transmission.…”

Section: Resultssupporting

confidence: 66%

Section: Mglu 4 Interacts With Mglu 2 To Form Hetero-complexes In Vitromentioning

confidence: 89%

“…In addition, this finding does not align with the ability of the structurally distinct mGlu 4 -selective PAM Lu AF21934 to potentiate mGlu 4 agonist effects at corticostriatal synapses (Bennouar et al, 2013). Interestingly, both the Group II mGlu agonist LY379268 (Picconi et al, 2002) and the mGlu 2 PAM cyPPTS inhibit excitatory transmission at corticostriatal synapses via a presynaptic mechanism of action, suggesting that mGlu 2 receptors are also expressed on corticostriatal terminals. Recent studies, including time-resolved FRET and coexpression studies, have shown that mGlu 2 and mGlu 4 form heterodimers in vitro (Doumazane et al, 2011;Kammermeier, 2012), and we hypothesized that mGlu 4 -containing heteromers may be expressed on corticostriatal terminals and may not display the same response to PHCCC as that observed with mGlu 4 homomers.…”

Section: Mglu 4 Interacts With Mglu 2 To Form Hetero-complexes In Vitromentioning

confidence: 89%

“…Previous immunohistochemistry and in situ hybridization studies suggest that mGlu 2 and mGlu 4 are colocalized in several brain regions (Ohishi et al, 1993(Ohishi et al, , 1995Neki et al, 1996;Bradley et al, 1999), and mGlu 2 is also functionally expressed at corticostriatal synapses . We tested the hypothesis that heterodimers of mGlu 2/4 may display a unique profile in response to selective mGlu 4 PAMs and that these mGlu subtypes form hetero-complexes in the striatum.…”

Section: Introductionmentioning

confidence: 97%

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Selective Actions of Novel Allosteric Modulators Reveal Functional Heteromers of Metabotropic Glutamate Receptors in the CNS

Shen¹,

et al. 2013

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Metabotropic glutamate (mGlu) receptors play important roles in regulating CNS function and are known to function as obligatory dimers. Although recent studies have suggested heterodimeric assembly of mGlu receptors in vitro, the demonstration that distinct mGlu receptor proteins can form heterodimers or hetero-complexes with other mGlu subunits in native tissues, such as neurons, has not been shown. Using biochemical and pharmacological approaches, we demonstrate here that mGlu 2 and mGlu 4 form a hetero-complex in native rat and mouse tissues which exhibits a distinct pharmacological profile. These data greatly extend our current understanding of mGlu receptor interaction and function and provide compelling evidence that mGlu receptors can function as heteromers in intact brain circuits.

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Section: Discussionsupporting

confidence: 87%

Section: Resultssupporting

confidence: 66%

Section: Mglu 4 Interacts With Mglu 2 To Form Hetero-complexes In Vitromentioning

confidence: 89%

Section: Mglu 4 Interacts With Mglu 2 To Form Hetero-complexes In Vitromentioning

confidence: 89%

Section: Introductionmentioning

confidence: 97%

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Selective Actions of Novel Allosteric Modulators Reveal Functional Heteromers of Metabotropic Glutamate Receptors in the CNS

Shen¹,

et al. 2013

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An mGlu4‐Positive Allosteric Modulator Alleviates Parkinsonism in Primates

et al. 2018

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Imaging metabotropic glutamate receptor system: Application of positron emission tomography technology in drug development

Xu¹,

2019

Medicinal Research Reviews

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The diversity seen in the mode of pharmacology and the numerous glutamate receptor subtypes have previously complicated drug development efforts. Nonetheless, recent clinical trials of drug candidates that accommodate the glutamatergic intricate pharmacology have yielded encouraging results. Target engagement is an important requirement for the advancement of central nervous system drug candidates into clinical trial. Positron emission tomography (PET) tracer technology has the unique ability to give the direct insight into the relationship between the level of receptor occupancy and the administered dose, thus establishing a direct link between the level of target exposure and the drug efficacy in human. This review is focused on the advancement of mGlu5, mGlu 1, and mGlu 2 receptor‐related PET tracer technology: PET tracer development strategies, PET tracer selection in receptor occupancy studies, the scopes and limitations to use PET to measure receptor occupancy for the drug candidates with different pharmacology, and how to use the measurements of receptor occupancy as a translational biomarker for decision‐making in an innovative drug development program.

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Synergy between l-DOPA and a novel positive allosteric modulator of metabotropic glutamate receptor 4: Implications for Parkinson's disease treatment and dyskinesia

Cited by 87 publications

References 62 publications

Selective Actions of Novel Allosteric Modulators Reveal Functional Heteromers of Metabotropic Glutamate Receptors in the CNS

Selective Actions of Novel Allosteric Modulators Reveal Functional Heteromers of Metabotropic Glutamate Receptors in the CNS

An mGlu4‐Positive Allosteric Modulator Alleviates Parkinsonism in Primates

Imaging metabotropic glutamate receptor system: Application of positron emission tomography technology in drug development

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