Eight different types of mGluRs, labeled mGluR1 to mGluR8 (GRM1 toGRM8), are divided into groups I, II, and III.[1][3][4][8] Receptor types are grouped based on receptor structure and physiological activity.[2] The mGluRs are further divided into subtypes, such as mGluR7a and mGluR7b.
Group I mGluRs, but not other groups, are activated by3,5-dihydroxyphenylglycine (DHPG),[14] a fact that is useful to experimenters because it allows them to isolate and identify them.
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 ofcyclic adenosine monophosphate, or cAMP, by activating aG protein that inhibits the enzymeadenylyl cyclase, which forms cAMP fromATP.[1][3][4][17] These receptors are involved in presynaptic inhibition,[8] and do not appear to affect postsynaptic membrane potential by themselves. Receptors in groups II and III reduce theactivity of postsynaptic potentials, both excitatory and inhibitory, in the cortex.[4]
LY-341,495 andMGS-0039 are drugs that act as a selective antagonist blocking both of the group II metabotropic glutamate receptors, mGluR2 and mGluR3.[18]RO4491533 acts as a negativeallosteric modulator of mGluR2 and mGluR3.[19]
Different types of mGluRs are distributed differently in cells. For example, one study found that Group I mGluRs are located mostly on postsynaptic parts of cells, while groups II and III are mostly located on presynaptic elements,[14] though they have been found on both pre- and postsynaptic membranes.[8]
Also, different mGluR subtypes are found predominantly in different parts of the body. For example, mGluR4 is located only in the brain, in locations such as thethalamus,hypothalamus andcaudate nucleus.[20] All mGluRs except mGluR6 are thought to exist in thehippocampus andentorhinal cortex.[14]
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 ofN-methyl-D-aspartate receptors (NMDARs),[12][13] a type of ion channel-linked receptor that is central in aneurotoxic process calledexcitotoxicity. Proteins calledPDZ proteins frequently anchor mGluRs near enough to NMDARs to modulate their activity.[21]
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.[22] Excessive amounts ofN-methyl-D-aspartate (NMDA), the selective specific agonist of NMDARs, has been found to cause more damage to neurons in the presence of group I mGluR agonists.[23] On the other hand, agonists of group II[24] and III mGluRs reduce NMDAR activity.[15]
Group II[25] and III[23] mGluRs tend to protect neurons from excitotoxicity,[15][26][27] possibly by reducing the activity of NMDARs.
Metabotropic glutamate receptors are also thought to affectdopaminergic andadrenergic neurotransmission.[28]
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.[31] 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 ofgeneralized anxiety disorder.[32] Also, some researchers have suggested that activation of mGluR4 could be used as a treatment forParkinson's disease.[33]Most recently, Group I mGluRs, have been implicated in the pathogenesis ofFragile X, a type ofautism,[34] and a number of studies are currently testing the therapeutic potential of drugs that modify these receptors.[35] There is also growing evidence that group II metabotropic glutamate receptor agonists may play a role in the treatment of schizophrenia. Schizophrenia is associated with deficits in cortical inhibitory interneurons that release GABA and synaptic abnormalities associated with deficits in NMDA receptor function.[36] These inhibitory deficits may impair cortical function via cortical disinhibition and asynchrony.[37] The drugLY354740 (also known asEglumegad, an mGlu2/3agonist) was shown to attenuate physiologic and cognitive abnormalities in animal and human studies of NMDA receptor antagonist andserotonergic hallucinogen effects,[38][39][40][41] supporting the subsequent clinical evidence of efficacy for an mGluR2/3 agonist in the treatment of schizophrenia.[42]The same drug has been shown to interfere in thehypothalamic–pituitary–adrenal axis, with chronic oral administration of this drug leading to markedly reduced baselinecortisol levels in bonnet macaques (Macaca radiata); acute infusion ofLY354740 resulted in a marked diminution ofyohimbine-inducedstress response in those animals.[43]LY354740 has also been demonstrated to act on themetabotropic glutamate receptor 3 (GRM3) of humanadrenocortical cells, downregulatingaldosterone synthase,CYP11B1, and the production ofadrenalsteroids (i.e.aldosterone andcortisol).[44]
The first demonstration that glutamate could induce the formation of molecules belonging to a major second messenger system was in 1985, when it was shown that it could stimulate the formation ofinositol phosphates.[45] This finding allowed in 1987 to yield an explanation for oscillatory ionic glutamate responses and to provide further evidence for the existence of metabotropic glutamate receptors.[46] In 1991 the first metabotropic glutamate receptor of the seven transmembrane domain family was cloned.[47] More recent reports on ionotropic glutamate receptors able to couple to metabotropic transduction systems[48][49] suggest that metabotropic responses of glutamate might not be limited to seven transmembrane domain metabotropic glutamate receptors.
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