Metabotropic glutamate receptor
The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor which are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs. Like all glutamate receptors, mGluRs bind to glutamate, an amino acid that functions as an excitatory neurotransmitter.
Additional recommended knowledge
Function and structure
The mGluRs perform a variety of functions in the central and peripheral nervous systems: for example, they are involved in learning, memory, anxiety, and the perception of pain. They are found in pre- and postsynaptic neurons in synapses of the hippocampus, cerebellum, and the cerebral cortex, as well as other parts of the brain and in peripheral tissues.
Like other metabotropic receptors, mGluRs have seven transmembrane domains that span the cell membrane. Unlike ionotropic receptors, metabotropic receptors are not directly linked to ion channels, but may affect them by activating biochemical cascades. In addition to producing excitatory and inhibitory postsynaptic potentials, mGluRs serve to modulate the function of other receptors (such as NMDA receptors), changing the synapse's excitability.
Metabotropic glutamate receptors can cause Ca2+ to be released from intracellular structures in which it is stored, such as the endoplasmic reticulum (ER). Activation of mGluRs causes the production of Inositol trisphosphate, which activates receptors on the ER that open Ca2+-permeable channels.
Eight different types of mGluRs, labeled mGluR1 to mGluR8 (GRM1 to GRM8), are divided into groups I, II, and III. Receptor types are grouped based on receptor structure and physiological activity. The mGluRs are further divided into subtypes, such as mGluR7a and mGluR7b.
Overview of glutamate receptors
|| Receptors 
| Group I
|| GRM1 || Gq, ↑Na+, ↑K+, ↓glutamate
|| GRM5 || Gq, ↑Na+, ↑K+, ↓glutamate
| Group II
|| GRM2 || Gi/G0
|| GRM3 || Gi/G0
| Group III
|| GRM4 || Gi/G0
|| GRM6 || Gi/G0
|| GRM7 || Gi/G0
|| GRM8 || Gi/G0
The mGluRs in group I, including mGluR1 and mGluR5, are stimulated most strongly by the excitatory amino acid analog L-quisqualic acid. Stimulating the receptors causes an associated phospholipase C molecule to hydrolyze phosphoinositide phospholipids in the cell's plasma membrane.
These receptors are also associated with Na+ and K+ channels. Their action can be excitatory, increasing conductance, causing more glutamate to be released from the presynaptic cell, but they also increase inhibitory postsynaptic potentials, or IPSPs. They can also inhibit glutamate release and can modulate voltage-dependent calcium channels.
Group I mGluRs, but not other groups, are activated by 3,5-dihydroxyphenylglycine (DHPG), a fact which is useful to experimenters because it allows them to isolate and identify them.
Group II & Group III
The receptors in group II, including mGluRs 2 and 3, and group III, including mGluRs 4, 6, 7, and 8, (with some exceptions) prevent the formation of cyclic adenosine monophosphate, or cAMP, by activating a G protein that inhibits the enzyme adenylyl cyclase, which forms cAMP from ATP. These receptors are involved in presynaptic inhibition, and do not appear to affect postsynaptic membrane potential by themselves. Receptors in groups II and III reduce the activity of postsynaptic potentials, both excitatory and inhibitory, in the cortex.
The chemical 2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) activates only group II mGluRs, and 2-amino-4-phosphonobutyrate (L-AP4) activates only group III mGluRs.
Different types of mGluRs are distributed differently in cells. For example, one study found that Group I mGluRs are mostly located on postsynaptic parts of cells while groups II and III are mostly located on presynaptic elements, though they have been found on both pre- and postsynaptic membranes.
Also, different mGluR subtypes are found predominantly in different parts of the body. For exaple, mGluR4 is located only in the brain, in locations such as the thalamus, hypothalamus and caudate nucleus. All mGluRs except mGluR6 are thought to exist in the hippocampus and entorhinal cortex.
It is thought that mGluRs play a role in a variety of different functions.
Modulation of other receptors
Metabotropic glutamate receptors are known to act as modulators of (affect the activity of) other receptors. For example, group I mGluRs are known to increase the activity of N-methyl-D-aspartate receptors, a type of ion channel-linked receptor that is central in a neurotoxic process called excitotoxicity. Proteins called PDZ proteins frequently anchor mGluRs near enough to NMDARs to modulate their activity. It has been suggested that mGluRs may act as regulators of neurons' vulnerability to excitotoxicity (a deadly neurochemical process involving glutamate receptor overactivation) through their modulation of NMDARs, the receptor most involved in that process. Excessive amounts of N-methyl-D-aspartate, an agonist for NMDARs, has been found to cause more damage to neurons in the presence of group I mGluR agonists.
On the other hand, agonists of group II and III mGluRs reduce NMDAR activity. Group II and III mGluRs tend to protect neurons from excitotoxicity, possibly by reducing the activity of NMDARs.
Metabotropic glutamate receptors are also thought to affect dopaminergic and adrenergic neurotransmission.
Role in plasticity
Like other glutamate receptors, mGluRs have been shown to be involved in synaptic plasticity. They participate in long term potentiation and long term depression, and they are removed from the synaptic membrane in response to agonist binding.
Roles in disease
Since metabotropic glutamate receptors are involved in a variety of functions, abnormalities in their expression can contribute to disease. For example, studies with mutant mice have suggested that mutations in expression of mGluR1 may be involved in the development of certain types of cancer.
In addition, manipulating mGluRs can be useful in treating some conditions. For example, clinical trial suggested that an mGlu2/3 agonist, LY354740, was effective in the treatment of generalized anxiety disorder. Also, some researchers have suggested that activation of mGluR4 could be used as a treatment for Parkinson's disease.
It was first suggested that mGluRs might exist in 1985, after it was noted that glutamate could stimulate phospholipase C through the activation of a receptor that did not belong to any of the ionotropic glutamate receptor families (NMDA, AMPA, or Kainate receptors. The suspicion that mGluRs existed was confirmed in 1987, and in 1991 the first mGluR was cloned.
- ^ a b c d e f Bonsi P, Cuomo D, De Persis C, Centonze D, Bernardi G, Calabresi P, Pisani A. Modulatory action of metabotropic glutamate receptor (mGluR) 5 on mGluR1 function in striatal cholinergic interneurons. Neuropharmacology. 2005;49 Suppl 1:104-13. PMID 16005029. Retrieved January 14, 2007.
- ^ a b Ohashi H, Maruyama T, Higashi-Matsumoto H, Nomoto T, Nishimura S, and Takeuchia Y. A Novel Binding Assay for Metabotropic Glutamate Receptors Using (3H) L-Quisqualic Acid and Recombinant Receptors., Verlag der Zeitschrift für Naturforschung, Tübingen (Journal of Biosciences). 2002 Mar-Apr;57(3-4):348-55. PMID 12064739. Available through web archive. Retrieved on January 25, 2007.
- ^ a b c Hinoi E, Ogita K, Takeuchi Y, Ohashi H, Maruyama T, Yoneda Y. Characterization with [3H]quisqualate of group I metabotropic glutamate receptor subtype in rat central and peripheral excitable tissues. Neurochemistry International. 2001 Mar;38(3):277-85. PMID 11099787. Retrieved January 14, 2007.
- ^ a b c d e f g h i j k l m Chu Z, Hablitz JJ. Quisqualate induces an inward current via mGluR activation in neocortical pyramidal neurons. Brain Research. 2000 Oct 6;879(1-2):88-92. PMID 11011009. Retrieved January 14, 2007.
- ^ a b Platt SR. The role of glutamate in central nervous system health and disease - A review. Veterinary Journal. 2007 Mar;173(2):278-86. PMID 16376594. Retrieved on January 14, 2007.
- ^ a b c d e f g h i Endoh T. Characterization of modulatory effects of postsynaptic metabotropic glutamate receptors on calcium currents in rat nucleus tractus solitarius. Brain Research. 2004 Oct 22;1024(1-2):212-24. PMID 15451384. Retrieved January 14, 2007.
- ^ a b If not otherwise specified in table:TABLE 1 Classification of the metabotropic glutamate (mGlu) receptors From the following article:
Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Chad J. Swanson, Mark Bures, Michael P. Johnson, Anni-Maija Linden, James A. Monn & Darryle D. Schoepp. Nature Reviews Drug Discovery 4, 131-144 (February 2005). doi:10.1038/nrd1630
- ^ Bates B, Xie Y, Taylor N, Johnson J, Wu L, Kwak S, Blatcher M, Gulukota K, Paulsen JE. Characterization of mGluR5R, a novel, metabotropic glutamate receptor 5-related gene. Brain Res Mol Brain Res. 2002 Dec 30;109(1-2):18-33. PMID 12531512. Retrieved January 14, 2007.
- ^ a b c d Shigemoto R, Kinoshita A, Wada E, Nomura S, Ohishi H, Takada M, Flor PJ, Neki A, Abe T, Nakanishi T, and Mizuno N. 1997. Differential Presynaptic Localization of Metabotropic Glutamate Receptor Subtypes in the Rat Hippocampus. Journal of Neuroscience, Volume 17, Issue 19, Pages 7503-7522. Retrieved September 5, 2007.
- ^ a b MRC (Medical Research Council), Glutamate receptors: Structures and functions., University of Bristol Centre for Synaptic Plasticity (2003). Retrieved January 14, 2007.
- ^ InterPro. InterPro: IPR001786 Metabotropic glutamate receptor 4. Retrieved on August 3, 2007.
- ^ Skeberdis VA, Lan J, Opitz T, Zheng X, Bennett MV, and Zukin RS. 2001. mGluR1-mediated potentiation of NMDA receptors involves a rise in intracellular calcium and activation of protein kinase C. Neuropharmacology, Volume 40, Issue 7, Pages 856-865. PMID 11378156. Retrieved on February 24, 2007.
- ^ Lea PM, Custer SJ, Vicini S and Faden AI. 2002. Neuronal and glial mGluR5 modulation prevents stretch-induced enhancement of NMDA receptor current. Pharmacology, Biochemistry, and Behavior, Volume 73, Issue 2, Pages 287-298. PMID 12117582. Retrieved on February 24, 2007.
- ^ Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P, Doan A, Aakalu VK, Lanahan AA, Sheng M, and Worley PF. 1999. Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron, Volume 23, Issue 3, Pages 583-592. PMID 10433269. Retrieved on February 24, 2007.
- ^ Baskys A and Blaabjerg M. 2005. Understanding regulation of nerve cell death by mGluRs as a method for development of successful neuroprotective strategies. Journal of the Neurological Sciences, Volumes 229-230, Pages 201-209. PMID 15760640. Retrieved on February 24, 2007.
- ^ a b Bruno V, Copani A, Knopfel T, Kuhn R, Casabona G, Dell'Albani P, Condorelli DF, and Nicoletti F. 1995. Activation of metabotropic glutamate receptors coupled to inositol phospholipid hydrolysis amplifies NMDA-induced neuronal degeneration in cultured cortical cells. Neuropharmacology, Volume 34, Issue 8, Pages 1089-1098. PMID 8532158. Retrieved on February 24, 2007.
- ^ Buisson A, Yu SP, and Choi DW. 1996. DCG-IV selectively attenuates rapidly triggered NMDA-induced neurotoxicity in cortical neurons. European Journal of Neuroscience, Volume 8, Issue 1, Pages 138-143. PMID 8713457. Retrieved on February 24, 2007.
- ^ a b Ambrosini A, Bresciani L, Fracchia S, Brunello N, and Racagni G. 1995. Metabotropic glutamate receptors negatively coupled to adenylate cyclase inhibit N-methyl-D-aspartate receptor activity and prevent neurotoxicity in mesencephalic neurons in vitro. Molecular Pharmacology, Volume 47, Issue 5, Pages 1057-1064. PMID 7746273. Retrieved on February 24, 2007.
- ^ Bruno V, Battaglia G, Copani A, Giffard RG, Raciti G, Raffaele R, Shinozaki H, and Nicoletti F. 1995. Activation of class II or III metabotropic glutamate receptors protects cultured cortical neurons against excitotoxic degeneration. European Journal of Neuroscience, Volume 7, Issue 9, Pages 1906-1913. PMID 8528465. Retrieved on February 24, 2007.
- ^ Allen JW, Ivanova SA, Fan L, Espey MG, Basile AS, and Faden AI. 1999a. Group II metabotropic glutamate receptor activation attenuates traumatic neuronal injury and improves neurological recovery after traumatic brain injury. Journal of Pharmacology and Experimental Therapeutics, Volume 290, Issue 1, Pages 112-120. PMID 10381766. Retrieved on February 24, 2007.
- ^ Faden AI, Ivanova SA, Yakovlev AG, and Mukhin AG. 1997. Neuroprotective effects of group III mGluR in traumatic neuronal injury. Journal of Neurotrauma, Volume 14, Issue 12, Pages 885-895. PMID 9475370. Retrieved on February 24, 2007.
- ^ Wang J-Q and Brownell A-L. 2007. Development of metabotropic glutamate receptor ligands for neuroimaging. Current Medical Imaging Reviews, Volume 3, Number 3, August 2007 , Pages 186-205. Retrieved on September 5, 2007.
- ^ Baskys A, Fang L, Bayazitov I. Activation of neuroprotective pathways by metabotropic group I glutamate receptors: a potential target for drug discovery? Annals of the New York Academy of Sciences. 2005 Aug;1053:55-73. PMID 16179509. Retrieved on January 14, 2007.
- ^ Namkoong J, Shin SS, Lee HJ, Marín YE, Wall BA, Goydos JS, Chen S. 2007. Metabotropic glutamate receptor 1 and glutamate signaling in human melanoma. Cancer Research, Volume 67, Issue 5, Pages 2298-2305. PMID 17332361. Retrieved on August 5, 2007.
- ^ Dunayevich E, Erickson J, Levine L, Landbloom R, Schoepp DD, Tollefson GD. 2007. Efficacy and Tolerability of an mGlu2/3 Agonist in the Treatment of Generalized Anxiety Disorder. Neuropsychopharmacology, published online ahead of print. PMID 17712352. Retrieved on August 5, 2007.
- ^ Marino MJ, Williams DL Jr, O'Brien JA, Valenti O, McDonald TP, Clements MK, Wang R, DiLella AG, Hess JF, Kinney GG, Conn PJ. 2003. Allosteric modulation of group III metabotropic glutamate receptor 4: a potential approach to Parkinson's disease treatment. Proceedings of the National Academy of Sciences of the USA, Volume 100, Issue 23, Pages 13668-13673. PMID 14593202. Retrieved on August 5, 2007.
- ^ a b Temple MD, O'Leary DM, and Faden AI. 2001. The role of glutamate receptors in the pathophysiology of traumatic central nervous system injury. Chapter 4. In, Head Trauma: Basic, Preclinical, and Clinical Directions. Miller LP and Hayes RL, eds. Co-edited by Newcomb JK. John Wiley and Sons, Inc. New York. Pages 87-113.
|Transmembrane receptor: G protein-coupled receptors|
|Class A: Rhodopsin like||Acetylcholine (M1, M2, M3, M4, M5) - Adrenergic (α1 (A, B, D), α2 (A, B, C), β1, β2, β3) - Adrenomedullin - Anaphylatoxin (C3a, C5a) - Angiotensin (1, 2) - Apelin - Bile acid - Bombesin (BRS3, GRPR, NMBR) - Bradykinin (B1, B2) - Cannabinoid (CB1, CB2) - Chemokine - Cholecystokinin (A, B) - Dopamine (D1, D2, D3, D4, D5) - Eicosanoid (CysLT (1, 2), LTB4 (1, 2), FPRL1, OXE, Prostaglandin ((DP (1, 2), EP (1, 2, 3, 4), PGF, Prostacyclin, Thromboxane) - EBI2 - Endothelin (A, B) - Estrogen - Formyl peptide (1, L1, L2) - Free fatty acid (1, 2, 3, 4) - FSH - Galanin (1, 2, 3) - Gonadotropin-releasing hormone (1, 2) - GPR (1, 3, 4, 6, 12, 15, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 31, 32, 33, 34, 35, 37, 39, 42, 44, 45, 50, 52, 55, 61, 62, 63, 65, 68, 75, 77, 78, 79, 82, 83, 84, 85, 87, 88, 92, 101, 103, 119, 120, 132, 135, 139, 141, 142, 146, 148, 149, 150, 151, 152, 153, 160, 161, 162, 171, 172, 173, 174, 176, 182) - Ghrelin - Histamine (H1, H2, H3, H4) - Kisspeptin - Luteinizing hormone/choriogonadotropin - Lysophospholipid (1, 2, 3, 4, 5, 6, 7, 8) - MAS (1, 1L, D, E, F, G, X1, X2, X3, X4) - Melanocortin (1, 2, 3, 4, 5) - MCHR (1, 2) - Melatonin (1A, 1B)- Motilin - neuromedin (B, U (1, 2)) - Neuropeptide (B/W (1, 2), FF (1, 2), S, Y (1, 2, 4, 5)) - Neurotensin (1, 2) - Opioid (Delta, Kappa, Mu, Nociceptin, but not Sigma) - Olfactory - Opsin (3, 4, 5, 1LW, 1MW, 1SW, RGR, RRH) - Orexin (1, 2) - Oxytocin - Oxoglutarate - PAF - Prokineticin (1, 2) - Prolactin-releasing peptide - Protease-activated (1, 2, 3, 4) - Purinergics (Adenosine (A1, A2a, A2b, A3), P2Y, (1, 2, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14)) - Relaxin (1, 2, 3, 4) - Somatostatin (1, 2, 3, 4, 5) - Serotonin, all but 5-HT3 (5-HT1 (A, B, D, E, F), 5-HT2 (A, B, C), 5-HT (4, 5A, 6, 7)) - SREB - Succinate - TAAR (1, 2, 3, 5, 6, 8, 9) - Tachykinin (1, 2, 3) - Thyrotropin - Thyrotropin-releasing hormone - Urotensin-II - Vasopressin (1A, 1B, 2)|
|Class B: Secretin like||Brain-specific angiogenesis inhibitor (1, 2, 3) - Cadherin (1, 2, 3) - Calcitonin - CD97 - Corticotropin-releasing hormone (1, 2) - EMR (1, 2, 3) - Glucagon (GR, GIPR, GLP1R, GLP2R) - Growth hormone releasing hormone - PACAPR1- GPR (56, 64, 97, 98, 110, 111, 112, 113, 114, 115, 116, 123, 124, 125, 126, 128, 133, 143, 144, 157) - Latrophilin (1, 2, 3, ELTD1) - Parathyroid hormone (1, 2) - Secretin - Vasoactive intestinal peptide (1, 2)|
|Class C: Metabotropic glutamate / pheromone||Calcium-sensing receptor - GABA B (1, 2) - Glutamate receptor (Metabotropic glutamate (1, 2, 3, 4, 5, 6, 7, 8)) - GPRC6A - GPR (156, 158, 179) - RAIG (1, 2, 3, 4) - Taste receptors (TAS1R (1, 2, 3) TAS2R (1, 3, 4, 5, 8, 9, 10, 12, 13, 14, 16, 38, 39, 40, 41, 43, 44, 45, 46, 47, 48, 49, 50))|
|Frizzled / Smoothened||Frizzled (1, 2, 3, 4, 5, 6, 7, 8, 9, 10) - Smoothened|