Allosteric modulation of metabotropic glutamate receptor 5 affects phosphorylation, internalization, and desensitization of the μ-opioid receptor

Schröder, Helmut; Wu, Di; Seifert, Anja; Ranković, M.; Schulz, Stefan; Höllt, Volker; Koch, Thomas

doi:10.1016/j.neuropharm.2008.12.010

Cited by 52 publications

(42 citation statements)

References 60 publications

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“…Co-internalization of co-expressed receptors has been observed in a substantial number of cases. For example, the -opioid receptor agonist [D-Ala 2 ,N-MePhe 4 ,Gly-ol]enkephalin is able to cause internalization of the mGluR5 as well as the -opioid receptor when the two receptors are co-expressed, whereas the non-competitive mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine limits [D-Ala 2 ,NMePhe 4 ,Gly-ol]enkephalin-induced internalization of the -opioid receptor (51). Similarly, interactions between purinergic P2Y11 and P2Y1 receptors are reported to allow agonist internalization of P2Y11, although this receptor is not generally able to be internalized in response to agonist when expressed in isolation (52).…”

Section: Discussionmentioning

confidence: 99%

Heteromultimerization of Cannabinoid CB1 Receptor and Orexin OX1 Receptor Generates a Unique Complex in Which Both Protomers Are Regulated by Orexin A

Ward

Pediani

Milligan

2011

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Heteromultimerization of Cannabinoid CB1 Receptor and Orexin OX1 Receptor Generates a Unique Complex in Which Both Protomers Are Regulated by Orexin A

Ward

Pediani

Milligan

2011

Journal of Biological Chemistry

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“…The mGlu1a receptor variant can interact with the calcium-sensing receptor (CaR) (Gama et al 2001), Caveolin1/2b , the GB1 subunit of GABA B receptor (Tabata et al 2004), and the Ca v2.1 pore-forming subunit of voltage-gated calcium channels (Kitano et al 2003). Coassembly of mGlu5 receptor with N-methyl-D-aspartate (NMDA) (Perroy et al 2008) and m-opioid receptors (Schroder et al 2009) has also been described (Table 3.1). Such a complexity of receptor associations gives rise to diversity of intracellular signalings.…”

Section: Membrane Proteinsmentioning

confidence: 99%

Diversity of Metabotropic Glutamate Receptor–Interacting Proteins and Pathophysiological Functions

Fagni

2012

Synaptic Plasticity

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In the mammalian brain, the large majority of excitatory synapses express pre- and postsynaptic glutamate receptors. These are ion channels and G protein-coupled membrane proteins that are organized into functional signaling complexes. Here, we will review the nature and pathophysiological functions of the scaffolding proteins associated to these receptors, focusing on the G protein-coupled subtypes.

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“…Based on these reports and evidence for a MOR-mGluR 5 heteromer in cultured cells (Schröder et al, 2009), a bivalent ligand (MMG22) that contains a mu opioid agonist and mGluR 5 antagonist pharmacophores was developed (Akgün et al, 2013). MMG22 displayed exceptionally potent antinociception upon intrathecal (i.t.)…”

Section: Introductionmentioning

confidence: 99%

Targeting putative mu opioid/metabotropic glutamate receptor-5 heteromers produces potent antinociception in a chronic murine bone cancer model

Smeester

Lunzer

Akgün

et al. 2014

European Journal of Pharmacology

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The therapeutic management of chronic pain associated with many cancers is problematic due to development of tolerance and other adverse effects during the disease progression. Recently we reported on a bivalent ligand (MMG22) containing both mu agonist and mGluR5 antagonist pharmacophores that produced potent antinociception in mice with LPS-induced acute inflammatory pain via a putative MOR-mGluR5 heteromer. In the present study we have investigated the antinociception of MMG22 in a mouse model of bone cancer pain to determine its effectiveness in reducing this type of chronic nociception. There was a 572-fold increase in the potency of MMG22 over a period of 3–21 days that correlated with the progressive increase in hyperalgesia induced by bone tumor growth following implantation of fibrosarcoma cells in mice. The enhancement of antinociception with the progression of the cancer is possibly due to inhibition of NMDA receptor-mediated hyperalgesia via antagonism of mGluR5 and concomitant activation of MOR by the MMG22-occupied heteromer. Notably, MMG22 was 3.6-million-fold more potent than morphine at PID 21. Since MMG22 exhibited a 250,000-times greater potency than that of a mixture of the mu opioid (M19) agonist and mGluR5 antagonist (MG20) monovalent ligands, the data suggest that targeting the putative MOR-mGluR5 heteromer is far superior to univalent interaction with receptors in reducing tumor-induced nociception. In view of the high potency, long duration (>24 h) of action and minimal side effects, MMG22 has the potential to be a superior pharmacological agent than morphine and other opiates in the treatment of chronic cancer pain and to serve as a novel pharmacologic tool.

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Allosteric modulation of metabotropic glutamate receptor 5 affects phosphorylation, internalization, and desensitization of the μ-opioid receptor

Cited by 52 publications

References 60 publications

Heteromultimerization of Cannabinoid CB1 Receptor and Orexin OX1 Receptor Generates a Unique Complex in Which Both Protomers Are Regulated by Orexin A

Heteromultimerization of Cannabinoid CB1 Receptor and Orexin OX1 Receptor Generates a Unique Complex in Which Both Protomers Are Regulated by Orexin A

Diversity of Metabotropic Glutamate Receptor–Interacting Proteins and Pathophysiological Functions

Targeting putative mu opioid/metabotropic glutamate receptor-5 heteromers produces potent antinociception in a chronic murine bone cancer model

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