Metabotropic glutamate receptor

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 (Bonsi et al., 2005). Like all glutamate receptors, mGluRs bind to glutamate, an amino acid that functions as an excitatory neurotransmitter.

The mGluRs are found in pre- and postsynaptic neurons in synapses of the hippocampus, cerebellum (Hinoi et al., 2001), and the cerebral cortex, as well as other parts of the brain and peripheral tissues (Chu and Hablitz, 2000).

Like other metabotropic receptors, mGluRs have seven transmembrane domains that span the cell membrane (Platt, 2005). 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 (Chu and Hablitz, 2000; Endoh, 2004; Bonsi et al., 2005, Platt, 2005).

Eight different types of mGluRs, labeled mGluR1 to mGluR8, are divided into groups I, II, and III (Chu and Hablitz, 2000; Hinoi et al., 2001; Endoh, 2004; Bonsi et al., 2005).

Group I

The mGluRs in group I, including mGluR1 and mGluR5, are stimulated most strongly by the excitatory amino acid analog L-quisqualic acid (Chu and Hablitz, 2000; Bates et al., 2002). Stimulating the receptors causes an associated phospholipase C molecule to hydrolyze phosphoinositide phospholipids in the cell's plasma membrane (Chu and Hablitz, 2000; Endoh, 2004; Bonsi et al., 2005).

These receptors, which are usually found on postsynaptic membranes (Endoh, 2004), are also associated with Na⁺ channels and K⁺ channels (Chu and Hablitz, 2000). 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 (Chu and Hablitz, 2000). They can also inhibit glutamate release and can modulate voltage-dependent calcium channels (Endoh, 2004).

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 (Chu and Hablitz, 2000; Hinoi et al., 2001; MRC, 2003; Bonsi et al., 2005). Found on both pre- and postsynaptic membranes, these receptors are involved in presynaptic inhibition (Endoh, 2004), 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 (Chu and Hablitz, 2000).

Role in plasticity and neuroprotection

Like other glutamate receptors, mGluRs have been shown to be involved in synaptic plasticity (Endoh, 2004; Bonsi et al., 2005) and in neurotoxicity/neuroprotection[1][2]. They participate in long term potentiation and long term depression, and they are removed from the synaptic membrane in response to agonist binding (MRC, 2003).

History

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; Temple et al, 2001). The suspicion that mGluRs existed was confirmed in 1987, and in 1991 the first mGluR was cloned (Temple et al, 2001).

References

• 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
• 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
• Chu Z, Hablitz JJ. Quisqualate induces an inward current via mGluR activation in neocortical pyramidal neurons. Brain Res. 2000 Oct 6;879(1-2):88-92. PMID 11011009
• Endoh T. Characterization of modulatory effects of postsynaptic metabotropic glutamate receptors on calcium currents in rat nucleus tractus solitarius. Brain Res. 2004 Oct 22;1024(1-2):212-24. PMID 15451384
• 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. Neurochem Int. 2001 Mar;38(3):277-85. PMID 11099787
• Kandel ER, Schwartz JH, Jessell TM. Principles of Neural Science, 4th ed., pp.178-180. McGraw-Hill, New York (2000). ISBN 0838577016
• MRC (Medical Research Counsil), Glutamate receptors: Structures and functions., University of Brisotol Centre for Synaptic Plasticity (2003).
• 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. znaturforsch.com (2002).
• Siliprandi R, Lipartiti M, Fadda E, Sautter J, Manev H. Activation of the glutamate metabotropic receptor protects retina against N-methyl-D-aspartate toxicity. Eur J Pharmacol. 1992 Aug 14;219(1):173-4. PMID 1397046
• Temple MD, O'Leary DM, and Faden AI. 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. (2001). pp. 87- 113.

External links

• IUPHAR GPCR Database - Metabotropic Glutamate Receptors