Shifting towards a model of mGluR5 dysregulation in schizophrenia: Consequences for future schizophrenia treatment

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Metabotropic glutamate receptor subtype 5 (mGluR5), encoded by the GRM5 gene, represents a compelling novel drug target for the treatment of schizophrenia. mGluR5 is a postsynaptic G-protein coupled glutamate receptor strongly linked with several critical cellular processes that are reported to be disrupted in schizophrenia. Accordingly, mGluR5 positive allosteric modulators show encouraging therapeutic potential in preclinical schizophrenia models, particularly for the treatment of cognitive dysfunctions against which currently available therapeutics are largely ineffective. More work is required to support the progression of mGluR5-targeting drugs into the clinic for schizophrenia treatment, although some obstacles may be overcome by comprehensively understanding how mGluR5 itself is involved in the neurobiology of the disorder. Several processes that are necessary for the regulation of mGluR5 activity have been identified, but not examined, in the context of schizophrenia. These processes include protein–protein interactions, dimerisation, subcellular trafficking, the impact of genetic variability or mutations on protein function, as well as epigenetic, post-transcriptional and post-translational processes. It is essential to understand these aspects of mGluR5 to determine whether they are affected in schizophrenia pathology, and to assess the consequences of mGluR5 dysfunction for the future use of mGluR5-based drugs. Here, we summarise the known processes that regulate mGluR5 and those that have already been studied in schizophrenia, and discuss the consequences of this dysregulation for current mGluR5 pharmacological strategies.

This article is part of the Special Issue entitled ‘Metabotropic Glutamate Receptors, 5 years on’.

Graphical abstract

Summary of the processes regulating GRM5/mGluR5. GRM5 is regulated by epigenetic mechanisms (such as DNA methylation) and transcriptional mechanisms, such as regulation by micro RNA subtype 128a (miR-128a). At the protein level, mGluR5 signalling is regulated by both G-protein dependent (Gα) and independent (protein–protein interactions) mechanisms, which play an important role in neuronal calcium regulation. The mechanisms underlying mGluR5 post-translational modifications, splice variants, dimerisation, neuronal/brain region distributions and subcellular distributions in both healthy states and in schizophrenia pathology are not well understood.

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