Metabotropic glutamate receptors

Overview of the structure and function of metabotropic glutamate receptors

​Metabotropic glutamate receptors (mGluRs) are class C, G-protein-coupled receptors (GPCRs) in the CNS that play a role in modulating synaptic transmission and neuronal excitability. 

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Introduction to metabotropic glutamate receptors

​​​Metabotropic glutamate receptors provide a mechanism through which glutamate can modulate cell excitability and synaptic transmission via second messenger signaling pathways. These receptors lack ion channels, and instead affect other channels through the activation of intermediate molecules called G-proteins1. 

Metabotropic gluatmate receptors are divided into three groups based on their sequence similarity, pharmacology and signaling mechanisms: group I (mGlu1 and mGlu5 receptors), Group II (mGlu2 and mGlu3 receptors) and Group III (mGlu4, mGlu6, mGlu7 and mGlu8 receptors)2.

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​Figure 1: Metabotropic glumatate receptor groups.
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Structure of metabotropic glutamate receptors

mGluRs consist of seven transmembrane-spanning domains, an extracellular N-terminal domain and an intracellular C-terminus. The N-terminal domain is formed by a pair of hinged domains, termed the Venus fly-trap domain, and is responsible for binding glutamate and activating the receptor3. The C-terminal is important in modulating G-protein-coupling (Figure 2).

Metabotropic glutamate receptor

Figure 2: Schematic structure of the metabotropic glutamate receptors. (Adapted from Kenny, P.J. & Markou, 2004)

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Metabotropic glutamate receptors groups and functions

​mGluRs function as neuromodulators that can modulate neuronal excitability or neurotransmitter release1,4. In general, Group I mGluRs increase neuron excitability, whereas Groups II and III tend to suppress neuronal excitability5. Group I mGluRs are coupled to Gαq proteins, and activate phospholipase C1. Groups II and III receptors are coupled to Gi/o proteins, leading to adenylyl cyclase inhibition and cAMP formation, limiting downstream protein kinase A (PKA) activation1.

Group I: mGlu1 and mGlu5 

Group I mGluRs are primarily located postsynaptically and function by stimulating phospholipase C (PLC) to increase levels of diacylglycerol and inositol triphosphate. This activates protein kinase C (PKC) and the release of intracellular Ca2+, ultimately inhibiting presynaptic K+ channels and delaying nerve terminal repolarization. Group I mGluRs can also activate a range of downstream effectors, which may be important in the regulation of synaptic plasticity1. 

mGlu5 receptors are an interesting therapeutic target for negative allosteric modulators as a potential therapy for depression, fragile X syndrome, anxiety, obsessive-compulsive disorders, and levodopa-induced dyskinesia in Parkinson's disease6.

Group II: mGlu2 and mGlu3

Group II mGluRs function presynaptically to suppress neuronal excitability through the inhibition of adenylate cyclase5. mGlu2 and mGlu3 subtypes share a high degree of sequence similarity and are highly expressed in the hippocampus, cortex, nucleus accumbens, striatum and amygdala7. These receptors are potential novel targets in the treatment of anxiety disorders and schizophrenia8–10.​

Group I mGluRs are primarily located postsynaptically and function by stimulating phospholipase C (PLC) to increase levels of diacylglycerol and inositol triphosphate. This activates protein kinase C (PKC) and the release of intracellular Ca2+, ultimately inhibiting presynaptic K+ channels and delaying nerve terminal repolarization. Group I mGluRs can also activate a range of downstream effectors, which may be important in the regulation of synaptic plasticity1. 

mGlu5 receptors are an interesting therapeutic target for negative allosteric modulators as a potential therapy for depression, fragile X syndrome, anxiety, obsessive-compulsive disorders, and levodopa-induced dyskinesia in Parkinson's disease6.

​Group III: mGlu4, mGlu6, mGlu7 and mGlu8

Group III mGluRs function in the same manner as Group II, being expressed presynaptically and suppressing neuronal excitability by inhibiting adenylate cyclase5. mGlu4 and mGlu7 receptors are widely distributed in the brain7, mGlu6 receptors are localized to the retina11, and mGlu8 receptors are primarily found at low levels in the hippocampus, hypothalamus and olfactory bulb7. Group III mGluRs play a role in synaptic remodeling and persistent drug seeking and addiction, exerting their effect via an as yet undefined presynaptic mechanism – possibly also extending to postsynaptic modulation12.

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​References

1. Niswender, C. M. & Conn, P. J. Metabotropic Glutamate Receptors: Physiology, Pharmacology, and Disease. Annu Rev Pharmacol Toxicol 50, 295–322 (2010).

2. Alexander, S. P. H. et al. The Concise Guide to Pharmacology 2013/14: G protein-coupled receptors. Br. J. Pharmacol. 170, 1459–581 (2013).

3. Pin, J. P., Galvez, T. & Prézeau, L. Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors. Pharmacol. Ther. 98, 325–354 (2003).

4. Pinheiro, P. S. & Mulle, C. Presynaptic glutamate receptors: physiological functions and mechanisms of action. Nat. Rev. Neurosci. 9, 423–436 (2008).

5. Pin, J.-P. et al. Metabotropic glutamate receptors, introduction. IUPHAR/BPS Guide to PHARMACOLOGY (2015). at 

6. Jaeschke, G. et al. Metabotropic glutamate receptor 5 negative allosteric modulators: discovery of 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (basimglurant, RO4917523), a promising novel medicine for psychiatric diseases. J. Med. Chem. 58, 1358–71 (2015).

7. Hovelsø, N. et al. Therapeutic potential of metabotropic glutamate receptor modulators. Curr. Neuropharmacol. 10, 12–48 (2012).

8. Swanson, C. J. et al. Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat. Rev. Drug Discov. 4, 131–144 (2005).

9. Conn, P. J., Lindsley, C. W. & Jones, C. K. Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia. Trends Pharmacol. Sci. 30, 25–31 (2009).

10. Patil, S. T. et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat. Med. 13, 1102–7 (2007).

11. Nakajima, Y. et al. Molecular characterization of a novel retinal metabotropic glutamate receptor mGluR6 with a high agonist selectivity for L-2-amino-4- phosphonobutyrate. J. Biol. Chem. 268, 11868–11873 (1993).

12. Mao, L., Guo, M., Jin, D., Xue, B. & Wang, J. Q. Group III metabotropic glutamate receptors and drug addiction. Front. Med. 7, 445–451 (2013).

13. Kenny, P. J. & Markou, A. The ups and downs of addiction: Role of metabotropic glutamate receptors. Trends Pharmacol. Sci. 25, 265–272 (2004).