Metabotropic glutamate receptor 3 (mGluR3) is an inhibitoryGi/G0-coupledG-protein coupled receptor (GPCR)[4] generally localized to presynaptic sites ofneurons in classical circuits.[5] However, in higher cortical circuits in primates, mGluR3 are localized post-synaptically, where they strengthen rather than weaken synaptic connectivity.[6] In humans, mGluR3 is encoded by theGRM3gene.[7][8] Deficits in mGluR3 signaling have been linked to impaired cognition in humans,[9] and to increased risk of schizophrenia,[10] consistent with their expanding role in cortical evolution.
In humans, mGluR3 is encoded by the GRM3 gene on chromosome 7. At least five protein-coding isoforms are predicted based on genomic information. The mGluR3 protein is a seven-pass transmembrane protein.
L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The metabotropic glutamate receptors are a family of G protein-coupled receptors, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group I includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3 while Group III includes GRM4, GRM6, GRM7 and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities.[8]
mGluR3 assumes an expanded role in the primate association cortex, where it supports higher cognitive functions. In rodents, mGluR3 are located primarily at presynaptic terminals, where they inhibit glutamate release.[11] By contrast, in the primateprefrontal cortex[12] andentorhinal cortex,[13] mGluR3 are predominantly postsynaptic, residing on dendritic spines where they regulate the cAMP-driven activation of calcium signaling.[12]
Feedforward cAMP–calcium signaling can open nearby potassium channels, reducing synaptic efficacy and impairing cognition—a phenomenon termed dynamic network connectivity.[14] mGluR3 counteract this process by closing potassium channels and thereby strengthening the functional connectivity of prefrontal cortical networks.In addition to responding to glutamate, mGluR3 are also activated byN-acetylaspartylglutamic acid (NAAG), which is co-released with glutamate but selectively stimulates mGluR3.[15] Levels of NAAG in the cerebrospinal fluid correlate with cognitive performance.[16] During neuroinflammation, the enzymeglutamate carboxypeptidase II (GCPII) degrades NAAG, thereby impairing prefrontal cortical cognitive function.[17] A gain-of-function variant in the gene encoding GCPII has been linked to cognitive impairment in humans.[18]
A mutation in the Kozak sequence in the 1st exon of the GRM3 gene was shown to change translation and transcription of cloned GRM3 gene constructs and was significantly associated with bipolar disorder with an odds ratio of 4.4.[19] Subsequently, a marker in GRM3 was implicated in a large genome-wide association study of schizophrenia with statistical significance of p<10−9.[21] A follow-up study of the Kozak sequence variant showed that it was associated with increased risk of bipolar disorder, schizophrenia and alcoholism.[22] The mGluR3 receptor encoded by GRM3 is targetable by several drugs that have been used in previous trials of schizophrenia and anxiety disorder. The agonist, antagonist and allosteric modulator drugs of mGluR3 can now be explored as new treatments for mental illness.[19] Other scientific evidence has been published which shows that the well established anti-manic drug lithium carbonate also changes GRM3 gene expression in themouse brain after treatment with lithium carbonate.[23]
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