Metabotropic glutamate receptors | SpringerLink

Cell Tissue Res (2006) 326:483–504 DOI 10.1007/s00441-006-0266-5

REVIEW

Metabotropic glutamate receptors Francesco Ferraguti & Ryuichi Shigemoto

Received: 23 April 2006 / Accepted: 31 May 2006 / Published online: 18 July 2006 # Springer-Verlag 2006

Abstract Metabotropic glutamate receptors (mGlus) are a family of G-protein-coupled receptors activated by the neurotransmitter glutamate. Molecular cloning has revealed eight different subtypes (mGlu1-8) with distinct molecular and pharmacological properties. Multiplicity in this receptor family is further generated through alternative splicing. mGlus activate a multitude of signalling pathways important for modulating neuronal excitability, synaptic plasticity and feedback regulation of neurotransmitter release. In this review, we summarize anatomical findings (from our work and that of other laboratories) describing their distribution in the central nervous system. Recent evidence regarding the localization of these receptors in peripheral tissues will also be examined. The distinct regional, cellular and subcellular distribution of mGlus in the brain will be discussed in view of their relationship to neurotransmitter release sites and of possible functional implications. Keywords Metabotropic glutamate receptor . Immunohistochemistry . Electron microscopy . Central nervous system . Peripheral localization

This work was supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan (R.S.) and by the Austrian Science Fund FWF (grant no. P16720 to F.F.). F. Ferraguti Department of Pharmacology, Innsbruck Medical University, Peter Mayr Strasse 1a, A-6020 Innsbruck, Austria R. Shigemoto (*) Division of Cerebral Structure, National Institute for Physiological Sciences, Myodaiji, Okazaki 444-8787, Japan e-mail: [email protected]

Introduction A large number of neurons and fibre systems in the central nervous system (CNS) have been shown to use the amino acid glutamate as their primary neurotransmitter (Watkins and Evans 1981; Fonnum 1984). Glutamate, like many other neurotransmitters, exerts its pleiotropic roles by means of multiple receptor proteins. Two main classes of glutamate receptors have been identified: ionotropic receptors, which are multimeric ion channels responsible for fast synaptic transmission, and metabotropic receptors (mGlus), which couple to G-proteins to modulate slow synaptic transmission through intracellular second messengers (Hollmann and Heinemann 1994; Nakanishi et al. 1998). The ability of the neurotransmitter glutamate to activate receptors coupled to heterotrimeric G-proteins was initially demonstrated in the mid-1980s by the evoked formation and increase in inositol mono, di- and tri-phosphate in striatal neurones in culture (Sladeczek et al. 1985). After that report, several other laboratories reproduced and confirmed the result in various brain preparations (Nicoletti et al. 1986a,b, 1987; Akiyama et al. 1987) and in Xenopus oocytes injected with rat brain mRNA (Sugiyama et al. 1987, 1989). Thus far, molecular cloning has revealed eight members of this family, termed metabotropic glutamate receptor 1 (mGlu1) to mGlu8 (also termed elsewhere mGluR1–8); these have been classified into three subgroups based on their sequence similarity, preferred signal transduction mechanisms and relative pharmacology (Conn and Pin 1997). Group I mGlus includes mGlu1 and mGlu5, which are coupled to phosphoinositide hydrolysis and are selectively activated by 3,5-dihydroxyphenylglycine (3,5DHPG); group II comprises mGlu2 and mGlu3, which in recombinant systems are negatively coupled to adenylate cyclase and have as a selective agonist LY379268; group III

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consists of mGlu4, mGlu6, mGlu7 and mGlu8, which are also negatively coupled to adenylate cyclase and are activated by 2-amino-4-phosphonobutyrate. The structure and function of mGlus has been reviewed in a number of recent articles and these are referred to the reader (De Blasi et al. 2001; Hermans and Challiss 2001; Schoepp 2001; Pin and Acher 2002; Conn 2003; Jingami et al. 2003; Spooren et al. 2003; Conn et al. 2005). In this introduction, we will only briefly describe some basic molecular, biochemical and physiological features of these receptors. The regional, cellular and subcellular distribution of mGlus in the brain will be reviewed in greater detail. We apologise for any omission of the existing literature because of space limitations. The putative mGlu topology includes a large N-terminal extracellular domain, three extracellular and three intracellular loops and a cytoplasmic C-terminal tail, separated by seven highly hydrophobic regions thought to span the lipid bilayer (Masu et al. 1991). The N-terminal portion of the receptor contains the glutamate-binding site (O’Hara et al. 1993; Okamoto et al. 1998; Jingami et al. 2003), whereas the intracellular domains physically interact with the G-proteins to initiate signal transduction events (Pin et al. 1994; Gomeza et al. 1996). Multiplicity in mGlus is further increased by the existence of splice variants. Alternative pre-mRNA splicing has indeed emerged in recent years as one of the most important and widespread mechanisms involved in the generation of transcript and protein diversity. Alternative splicing patterns

Fig. 1 Schematic drawing of mGlu alternative splice variants giving rise to the different translated isoforms and substantiated by their actual detection in tissues. Numbers right correspond to the length in amino acid residues. Different colours in the C-terminus indicate the changes in amino acid sequence between isoforms attributable to alternative splicing (TMD transmembrane domain). References reporting the identification of the respective isoforms: a Masu et al. 1991; b Tanabe et al. 1993; c Laurie et al. 1996; d Zhu et al. 1999; e Abe et al. 1992; f Minakami et al. 1995; g Sartorius et al. 2006; h Nakajima et al. 1993; i Valerio et al. 2001; j Okamoto et al. 1994; k Flor et al. 1997; l Corti et al. 1998; m Schulz et al. 2002; n Duvoisin et al. 1995; o Malherbe et al. 1999

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can result from the use of alternative 5′ or 3′ splice sites, alternative promoters and cleavage-polyadenylation sites, optional exons, mutually exclusive exons, cassette exons and retained introns. Many of these mechanisms have been shown to occur at mGlu genes. Within the mGlu family, alternatively spliced receptor variants have been reported and confirmed for mGlu1, mGlu3 and mGlu5-mGlu8 (see Fig. 1; Pin and Duvoisin 1995; Laurie et al. 1996; Flor et al. 1997; Corti et al. 1998; Malherbe et al. 1999; Zhu et al. 1999; Valerio et al. 2001; Schulz et al. 2002; Sartorius et al. 2006). Alternative splicing almost invariably occurs at the C-terminal domain, where it generally alters the carboxyl-terminal tail through exon skipping or the usage of alternative internal splice sites. For several mGlus (mGlu1E55, GRM3Δ4, mGlu6b, mGlu8c), short variants lacking the entire transmembrane domain, which could result in secreted proteins, have been identified. However, because these isoforms may retain the ability to dimerize with full-length receptors, they could be targeted as heterodimers to the plasma membrane, as suggested for GRM3Δ4 by immunohistochemical and fractionation data (Sartorius et al. 2006). Recent studies have shown that almost 50% of human genes possess alternative first exons and promoters (Kimura et al. 2006). Although the genomic structure of most mGlu subtypes remains to be determined, the use of three alternatively spliced first exons and multiple promoters has been shown for the human mGlu5 gene (Corti et al. 2003).

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mGlus have been implicated in many diverse functions of the mammalian CNS. These functions include the mediation of slow excitatory (Glaum and Miller 1992; McCormick and von Krosigk 1992; Eaton et al. 1993; Wu et al. 2004) and inhibitory (Fiorillo and Williams 1998) responses, the regulation of calcium channels (Swartz and Bean 1992; Sahara and Westbrook 1993; Chavis et al. 1994), potassium channels (Charpak et al. 1990; Shirasaki et al. 1994; Gereau and Conn 1995; Netzeband et al. 1997) and non-selective cation channels (Guerineau et al. 1995; Congar et al. 1997), the inhibition (Baskys and Malenka 1991; Desai and Conn 1991; Schrader and Tasker 1997; Wittmann et al. 2001; Xi et al. 2003; Acuna-Goycolea et al. 2004; Chu and Moenter 2005) and facilitation (Herrero et al. 1992; Rodriguez-Moreno et al. 1998; Morsette et al. 2001) of transmitter release, the induction of long-term potentiation (Bortolotto and Collingridge 1993; O’Connor et al. 1995; Manahan-Vaughan 1997; Raymond et al. 2000; Miura et al. 2002) and long-term depression (Linden et al. 1991; Kato 1993; Bolshakov and Siegelbaum 1994; Conquet et al. 1994; Shigemoto et al. 1994; Otani et al. 2002; Lin et al. 2000), the formation of various types of memory (Aiba et al. 1994; Packard et al. 2001), the regulation of trafficking of ionotropic glutamate receptors (Snyder et al. 2001; Lan et al. 2001), modification of Nmethyl-D-aspartate (NMDA) receptor-mediated synaptic transmission (Awad et al. 2000; Pisani et al. 2001; Guo et al. 2004; Harney et al. 2006) and the regulation of neuronal development (for reviews, see Pin and Duvoisin 1995; Hensch and Stryker 1996; Conn and Pin 1997; Kano et al. 1997; Plenz and Kitai 1998; Hannan et al. 2001; Catania et al. 2001). mGlus are also thought to be involved in various diseases such as seizure (Sansig et al. 2001), anxiety and stress disorders (Swanson et al. 2005; Linden et al. 2002), fragile X mental retardation (Bear et al. 2004), hypoxic brain damage (Poli et al. 2003) and excitotoxic neuronal death (Bruno et al. 2000). The coupling of mGlus to intracellular transduction pathways described in initial cloning studies was primarily established in heterologous cell lines transfected with the recombinant receptors. Therefore, it remains unclear which G-proteins and effector molecules are utilized in various neuronal cells in vivo. For example, group I mGlus are indeed coupled to phospholipase C with the subsequent production of inositol triphosphates, which induces intracellular calcium release in Purkinje cells (Yuzaki and Mikoshiba 1992; Takechi et al. 1998) and hippocampal CA1 neurons (Frenguelli et al. 1993) but the same receptor subtypes are also coupled to the inhibition of voltagedependent calcium channels in hippocampal neurons without intracellular diffusible messengers (Lester and Jahr 1990; Swartz and Bean 1992). In the latter case, activated G-proteins seem to interact directly with the calcium

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channels in a membrane-delimited manner. Group II mGlus can be coupled to the inhibition of cyclic AMP cascade in neuronal and glial cells (Baba et al. 1993; Prezeau et al. 1994) but are also linked to the rapid-onset regulation of various channels including calcium channels (Choi and Lovinger 1996) and G-protein-coupled inwardly rectifying K+ channels (GIRK) (Knoflach and Kemp 1998) depending on neuronal cell type (for a review, see Anwyl 1999). Except for mGlu6-mediated synaptic transmission to ON bipolar cells in the retina (Masu et al. 1995), group III mGlus mostly mediate the inhibition of neurotransmission (Trombley and Westbrook 1992; Jane et al. 1994) through the suppression of presynaptic voltage-dependent calcium channels (Takahashi et al. 1996). However, group III mGlus also seem to be involved in certain forms of synaptic plasticity, as reported in the cerebellum (Pekhletski et al. 1996) and basolateral amygdala (Neugebauer et al. 1997). Thus, mGlus in the three subgroups have a large variety of transduction mechanisms depending on the receptor subtype, the cell types in which they are expressed and the associated effector molecules. Whereas fast excitatory neurotransmission mediated by ionotropic glutamate receptors requires their localization principally in the postsynaptic membrane specialization of glutamatergic synapses, mGlus are found more widely distributed throughout various membrane compartments of both neuronal and glial cells. For example, the regulation of transmitter release mediated by mGlus is reported not only in glutamatergic synapses but also in GABAergic synapses (Desai and Conn 1991; Stefani et al. 1994; Poncer et al. 1995; Kinoshita et al. 1998; Bradley et al. 1999) and dopaminergic system (Hu et al. 1999). Furthermore, even in the glutamatergic system, the activation of mGlus by synaptically released glutamate often requires high-frequency or repetitive stimulation (Batchelor et al. 1994; Yokoi et al. 1996; Congar et al. 1997; Scanziani et al. 1997; Fiorillo and Williams 1998) possibly because of the extrasynaptic location of mGlus on dendrites and axons. These situations may also imply signal transmission between different synapses (heterosynaptic interaction) or different pathways mediated by spillover of glutamate activating mGlus remote from glutamate release sites (Ohishi et al. 1994; Wada et al. 1998; Vogt and Nicoll 1999). To understand the diversified physiological effects of glutamate, it is thus important to know the molecular identity of mGlus expressed in distinct subpopulations of neurons, the membrane compartments of neurons to which they are localized and the spatial relationship between mGlus and glutamate release sites of identified origins. In this review, the regional and cellular distribution of the eight mGlus in the mammalian CNS will be considered first and then the distinct subcellular localization of each mGlus and the relative functional implications will be discussed.

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Regional and cellular localization of mGlus in the CNS: a general view In situ hybridization and immunohistochemical studies have revealed distinct although partially overlapping patterns of the distribution of mRNA and immunoreactivity for the eight mGlu subtypes in the CNS (Fig. 2) not only in rodents, but also in primates (Hubert et al. 2001; Kaneda et al. 2003; Muly et al. 2003; Paquet and Smith 2003; Kuwajima et al. 2004). Striking differences in the regional and cellular distribution between splice variants of mGlu1 and mGlu7 have also been reported (Berthele et al. 1998; Corti et al. 1998; Ferraguti et al. 1998; Kinoshita et al. 1998; Alvarez et al. 2000; Mateos et al. 2000). The distribution of mGlu1, mGlu3, mGlu5 and mGlu7 is extensive throughout the brain, whereas that of mGlu2, mGlu4 and mGlu8 is more restricted to specific brain regions. Expression of mGlu6 has been found in the retina, but not in the brain or spinal cord (Nakajima et al. 1993; Nomura et al. 1994; Schools and Kimelberg 1999). In the adult rat, mGlus are mainly expressed in neuronal cells with the exception of mGlu3, which is also extensively expressed in glial cells throughout the brain (Ohishi et al.

Fig. 2 Distribution of mGlus in the adult rat brain (from Shigemoto and Mizuno 2000). Immunoreactivities for mGlu1α (mGluR1a), mGlu1 (mGluR1), mGlu2/3 (mGluR2/3), mGlu4a (mGluR4a), mGlu5 (mGluR5), mGlu7a (mGluR7a), mGlu7b (mGluR7b) and mGlu8 (mGluR8) in parasagittal sections (AOB accessory olfactory bulb, Acb accumbens nucleus, Cb cerebellum, Cx neocortex, GP globus pallidus, Hi hippocampus, IC inferior colliculus, LS lateral septum, MOB main olfactory bulb, OT olfactory tubercle, Pir piriform cortex, SC superior colliculus, SN substantia nigra, SpV spinal vestibular nucleus, St neostriatum, Th thalamus, VP ventral pallidum)

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1993b, 1994; Tanabe et al. 1993; Testa et al. 1994; Makoff et al. 1996a; Petralia et al. 1996a; Mineff and Valtschanoff 1999). Furthermore, the expression of mGlu3 and of mGlu5 has been found to be up-regulated in reactive astrocytes (Aronica et al. 2000; Ferraguti et al. 2001). Cultured astrocytes express mGlu4 in addition to mGlu3 and mGlu5 (Ciccarelli et al. 1997; Besong et al. 2002), whereas cultured microglia appear to express mGlu2, mGlu4, mGlu5, mGlu6 and mGlu8 (Biber et al. 1999; Taylor et al. 2003, 2005).

Distribution of group I mGlus Immunoreactivity for mGlu1 has been extensively found in the CNS, being most intense in Purkinje cells of the cerebellar cortex and mitral/tufted cells of the olfactory bulb (Martin et al. 1992; Shigemoto et al. 1992). Strong expression has also been detected in neurons of the lateral septum, globus pallidus, entopeduncular nucleus, ventral pallidum, magnocellular preoptic nucleus, most of the thalamic nuclei but not in the reticular nucleus, substantia nigra and dorsal cochlear nucleus (Martin et al. 1992;

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Hubert et al. 2001). Differential mRNA expression of mGlu1 splice variants has been observed in both rodent and human brain (Berthele et al. 1998, 1999); intense expression of mGlu1α has been found in Purkinje cells, mitral and tufted cells, hippocampal interneurons, thalamic neurons and neurons in the substantia nigra (Martin et al. 1992; Baude et al. 1993; Fotuhi et al. 1993; Ferraguti et al. 2004), whereas the mGlu1β splice variant is strongly expressed in CA3 hippocampal pyramidal neurons, granule cells of the dentate gyrus and lateral hypothalamus (Ferraguti et al. 1998; Mateos et al. 1998). At the electron-microscopic level, mGlu1 has been mostly detected in postsynaptic neuronal elements in the cerebral cortex (Ong et al. 1998), hippocampus (Baude et al. 1993; Lujan et al. 1996, 1997; Hanson and Smith 1999), striatum (Hanson and Smith 1999), thalamus (Martin et al. 1992; Godwin et al. 1996; Liu et al. 1998), hypothalamus (van den Pol et al. 1994), cerebellar cortex (Martin et al. 1992; Baude et al. 1993; Gorcs et al. 1993; Nusser et al. 1994; Lujan et al. 19961997; Jaarsma et al. 1998; Mateos et al. 2000) and dorsal cochlear nucleus (Petralia et al. 1996b; Jaarsma et al. 1998). A distribution largely complementary to that of mGlu1 has been observed throughout the CNS for the other member of group I mGlus, namely mGlu5. Intense expression has been seen mainly in telencephalic regions, including the cerebral cortex, hippocampus, subiculum, main and accessory olfactory bulbs, anterior olfactory nucleus, olfactory tubercle, striatum, nucleus accumbens and lateral septal nucleus (Abe et al. 1992; Shigemoto et al. 1993; Romano et al. 1995). In the hippocampus, mGlu5 is mainly expressed in dendritic fields of pyramidal and granule cells, whereas the cell layers are devoid of immunoreactivity (Shigemoto et al. 1997). Intense expression of mGlu5 has also been detected in some GABAergic interneurons in the neocortex and hippocampus (Kerner et al. 1997). In the brainstem, strong expression of mGlu5 has been detected in the shell regions of the inferior colliculus, superficial layers of the superior colliculus and caudal subnucleus of the spinal trigeminal nucleus. In the cerebellar cortex, only a small population (10%) of Golgi cells expresses mGlu5 and no expression has been detected in Purkinje cells or granule cells (Neki et al. 1996a; Negyessy et al. 1997). In the spinal cord, mGlu5 is strongly expressed in the superficial dorsal horn (Vidnyanszky et al. 1994; Berthele et al. 1999; Jia et al. 1999). Although the distribution of mGlu5a and mGlu5b appears largely similar, mGlu5a is found most abundantly in the young rat, whereas mGlu5b predominates in the adult rat (Joly et al. 1995; Romano et al. 1996). At the electron-microscopic level, mGlu5 has mainly been localized to somatic and dendritic profiles in the hippocampus (Lujan et al. 1996, 1997; Hanson and Smith 1999), basal ganglia (Shigemoto et al.

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1993; Hanson and Smith 1999), thalamus (Godwin et al. 1996; Liu et al. 1998), hypothalamus (Romano et al. 1995; van den Pol et al. 1995), cerebellar cortex (Negyessy et al. 1997), dorsal cochlear nucleus (Petralia et al. 1996b) and dorsal horn of the spinal cord (Vidnyanszky et al. 1994; Jia et al. 1999). In a few studies, mGlu5 immunoreactivity has been reported not only in somatodendritic domains of neurons, but also in axons (Romano et al. 1995) or vesiclecontaining profiles (Jia et al. 1999) and in astrocytes (van den Pol et al. 1995).

Distribution of group II mGlus The distribution of mGlu2 is more limited in the CNS than that of mGlu1, mGlu5 and mGlu3. The most intense expression of mGlu2 has been observed in Golgi cells in the cerebellar cortex (Ohishi et al. 1993a, 1994), mitral cells of the accessory olfactory bulb, external part of the anterior olfactory nucleus and some neurons in the entorhinal and parasubicular cortices. Moderate expression has been seen in the granule cells of the accessory olfactory bulb, some neurons in the neocortex, cingulate, retrosplenial and subicular cortices and the granule cells of the dentate gyrus, lateral, basolateral and basomedial amygdaloid nuclei, medial mammillary nucleus and anterior, ventrolateral, midline, intralaminar and centromedian-parafascicular thalamic nuclei (Ohishi et al. 1998). Although the distribution pattern of mGlu2-immunoreactive neuronal cell bodies (Ohishi et al. 1998) is in good accordance with that of mGlu2 mRNA (Ohishi et al. 1993a), mGlu2 has been located not only to somato-dendritic domains, but also to axonal domains of neurons (Hayashi et al. 1993; Neki et al. 1996b; Petralia et al. 1996a; Yokoi et al. 1996; Lujan et al. 1997; Shigemoto et al. 1997; Jaarsma et al. 1998; Liu et al. 1998; Testa et al. 1998; Wada et al. 1998; Cai and Pourcho 1999; Jia et al. 1999; Meguro et al. 1999). Neuropile containing immunoreactive axons and dendrites has been observed in various regions such as the accessory olfactory bulb, bed nucleus of the accessory olfactory tract, neocortex, cingulate, retrosplenial, subicular and entorhinal cortices, CA3 mossy fibre terminal zone, stratum-lacunosum moleculare of CA1 and CA3, molecular layer of the dentate gyrus, basolateral amygdaloid nucleus, striatum, nucleus accumbens, thalamic reticular nucleus, anteroventral and paraventricular thalamic nuclei, anterior and ventral tegmental nuclei, granular layer of the cochlear nucleus and parvicellular part of the lateral reticular nucleus. In the hippocampus, immunoreactivity for mGlu2 has mainly been found in the presynaptic structures of mossy fibres and perforant path. In the cerebellar cortex, the cell bodies, dendrites

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and axons of about 90% of the total population of Golgi cells show intense mGlu2 immunoreactivity. This population of Golgi cells is segregated from mGlu5-positive Golgi cells (Neki et al. 1996a). At the electron-microscopic level, immunoreactivity for mGlu2/3 has frequently been detected in small unmyelinated axons, especially in pre-terminal portions of axons, rather than in axon terminals (Yokoi et al. 1996; Shigemoto et al. 1997). No glial cells have been found to express mGlu2. mGlu3 is expressed extensively throughout the CNS (Ohishi et al. 1993b; Tanabe et al. 1993; Testa et al. 1994; Petralia et al. 1996a; Tamaru et al. 2001). Expression is marked in the olfactory tubercle, piriform cortex, neocortex, limbic cortex including the cingulate, retrosplenial, perirhinal, entorhinal and subicular cortical areas, molecular layer of the dentate gyrus, lateral septal nucleus, striatum, nucleus accumbens, lateral and basolateral amygdaloid nuclei, dorsal endopiriform nucleus, thalamic reticular nucleus, supraoptic nucleus, superficial layers of the superior colliculus, substantia nigra pars reticulata and Golgi cells in the cerebellar cortex, with expression being most prominent in the thalamic reticular nucleus neurons. Glial cells also express mGlu3 in many regions including the corpus callosum and anterior commissure. At the electron-microscopic level, immunoreactivity for mGlu3 has been observed not only in postsynaptic elements, but also in presynaptic elements and glial processes in the cerebral cortex, hippocampus and striatum (Tamaru et al. 2001).

Distribution of group III mGlus Amongst group III mGlus, the distribution of mGlu7 is the most extensive, whereas that of mGlu6 is mainly restricted to the retina (Nakajima et al. 1993; Kinoshita et al. 1998). The expression of mGlu4 is most intense in cerebellar granule cells (Kinoshita et al. 1996a). Prominent expression of mGlu4 has also been observed in the periglomerular cells and granule cells of the main olfactory bulb, olfactory tubercle, entorhinal cortex, CA1-3 and hilus of the hippocampus, lateral septum, septofimbrial nucleus, striatum, rostral part of the intercalated amygdaloid nucleus, thalamic nuclei, lateral mammillary nucleus, pontine nuclei and dorsal horn (Fotuhi et al. 1994; Testa et al. 1994; Makoff et al. 1996b; Kinoshita et al. 1998; Azkue et al. 2001; Corti et al. 2002). At the electron-microscopic level, mGlu4 immunoreactivity has been localized to the presynaptic active zone of varicosities of the parallel fibres in the molecular layer (Kinoshita et al. 1996a; Mateos et al. 1999). A presynaptic localization of mGlu4 has also been reported in the medial nucleus of the trapezoid body (Elezgarai et al. 1999), the inner third of the molecular

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layer of the dentate gyrus (Shigemoto et al. 1997), globus pallidus, substantia nigra pars reticulata and entopeduncular nucleus (Corti et al. 2002). In the hippocampus proper, mGlu4 labelling is prominent in the CA1-3 strata lacunosum moleculare and oriens. Somatodendritic profiles of some stratum oriens/alveus interneurones are richly decorated with mGlu4-labelled axon terminals making either type I or II synapses (Corti et al. 2002; Kogo et al. 2004). In the basal ganglia, both the direct and indirect striatal output pathways exhibit mGlu4-immunolabelled terminals forming mostly type II synapses on dendritic shafts (Bradley et al. 1999; Corti et al. 2002). The localization of mGlu4 on GABAergic terminals of striatal projection neurones suggests a role in heterosynaptic regulation. Expression of mGlu6 mRNA is restricted to the retina and no obvious expression has been detected in any other region of the brain (Nakajima et al. 1993). In the rat retina, expression of mGlu6 mRNA has been seen in the outer part of the inner nuclear layer (Nakajima et al. 1993; Akazawa et al. 1994; Hartveit et al. 1995) and mGlu6 immunoreactivity has been localized exclusively to the postsynaptic dendritic part of rod bipolar cells (Nomura et al. 1994). Prominent expression of mGlu7a has been detected in the main olfactory bulb, olfactory tubercle, neocortex, piriform cortex, hippocampus including CA1-CA3 and dentate gyrus, septum, striatum, accumbens nucleus, claustrum, amygdaloid complex, preoptic region, hypothalamus, thalamus, superior colliculus, locus coeruleus, dorsal cochlear nucleus and dorsal horn of the spinal cord (Kinzie et al. 1997; Shigemoto et al. 1997; Bradley et al. 1998; Corti et al. 1998; Kinoshita et al. 1998; Wada et al. 1998). Most intense expression is present in the tufted and mitral cells of the olfactory bulbs, medial septal nucleus neurons and locus coeruleus. The distribution of mGlu7b is more limited than that of mGlu7a (Corti et al. 1998); most regions showing mGlu7b immunoreactivity also display mGlu7a immunoreactivity (Shigemoto et al. 1997). On the contrary, many CNS regions showing mGlu7a immunoreactivity exhibit no mGlu7b immunoreactivity (Shigemoto et al. 1997). In the hippocampus, for example, mGlu7a is seen throughout all dendritic layers, whereas mGlu7b has been observed only in the terminal zone of the mossy fibres. Virtually all mGlu7b-positive structures are also mGlu7apositive (Kinoshita et al. 1998). Moreover, the expression of mGlu7a is higher than that of mGlu7b in the neocortex, anterior thalamus, medial geniculate nucleus and locus coeruleus. At the electron-microscopic level, both mGlu7a and mGlu7b have been observed almost exclusively in the presynaptic active zone in axon terminals (Bradley et al. 1996, 1998; Shigemoto et al. 1996, 1997; Kinzie et al. 1997; Kinoshita et al. 1998; Somogyi et al. 2003). mGlu7a has also been localized in axon terminals of primary afferent fibres terminating in laminae I and II of the spinal

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dorsal horn of the rat (Ohishi et al. 1995), in the islands of Calleja (Kinoshita et al. 1998), in layer I of the piriform cortex of the rat (Kinzie et al. 1997; Wada et al. 1998) and in corticostriatal, striatopallidal and striatonigral fibres in the basal ganglia (Kosinski et al. 1999). However, mGlu7 immunoreactivity has occasionally been seen in somatodendritic domains of neurons in the hippocampus, locus coeruleus, cerebellum, thalamic nuclei (Bradley et al. 1998), striatum and globus pallidus (Kosinski et al. 1999), a finding that remains to be confirmed. The expression pattern of mGlu8 is more restricted than that of mGlu7 (Duvoisin et al. 1995; Saugstad et al. 1997; Corti et al. 1998). Prominent mGlu8 expression has been observed in the main and accessory olfactory bulbs, anterior olfactory nucleus, piriform cortex, entorhinal cortex, pontine nuclei, and lateral reticular nucleus of the medulla oblongata. In the main olfactory bulb, mRNA expression is more intense in the mitral cell layer than in the granule cell layer, whereas it was more intense in the granule cell layer than in the mitral cell layer in the accessory olfactory bulb. Immunoreactivity for mGlu8 is marked in the terminal zones of the lateral perforant path, i.e. the outer layer of the CA3 stratum lacunosummoleculare and the outer one third of the molecular layer of the dentate gyrus, and superficial layers of the olfactory tubercle, piriform cortex and entorhinal cortex. Strong expression for mGlu8a has also been noted in scattered cells in the deeper layers of the cerebral cortex and pyramidal cells of the piriform cortex, whereas the olfactory tubercle virtually lacks mGlu8 immunoreactivity. In general, hybridization signals for mGlu8a are higher than those for mGlu8b in the majority of the brain regions; in some areas, such as the spinal vestibular nucleus, ambiguus nucleus and lateral nucleus of the medulla oblongata, only mGlu8a has been detected (Corti et al. 1998). Immunoreactivity for mGlu8a and mGlu8b is found entirely overlapping throughout rat telencephalic areas (Ferraguti et al. 2005). Electron microscopically, mGlu8a has been observed in the presynaptic active zone of axon terminals in layer Ia of the piriform cortex (Kinoshita et al. 1996b; Wada et al. 1998), CA1 stratum oriens of the hippocampus (Ferraguti et al. 2005) and molecular layer of the dentate gyrus (Shigemoto et al. 1997).

Cellular localization of mGlus in peripheral non-neural cells Although mGlus are predominantly expressed in nervous tissue, a number of recent studies have detected mGlus mRNA and protein in numerous other tissues under both physiological and pathological conditions. One of the first studies reporting the presence of mGlus in peripheral

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organs showed the ability of group I agonists to stimulate phosphoinositide hydrolysis in primary cultures of rat hepatocytes (Sureda et al. 1997). The expression of mGlu5, but not mGlu1, in rat liver was then demonstrated in a subsequent study (Storto et al. 2000a). Among group I mGlus, mGlu5 has been detected in several peripheral tissues including murine thymocytes, pinealocytes, melanocytes, pancreatic islets and rat testis (Yatsushiro et al. 1999; Frati et al. 2000; Gu and Publicover 2000; Storto et al. 2000b, 2001; Brice et al. 2002). Conversely, the expression of mGlu1 in non-neural cells seems so far to be limited to CD4/CD8 double-negative mouse thymocytes (Storto et al. 2000b), rat testis (Storto et al. 2001) and primary cultures of rat osteoblasts, although the lastmentioned only express the mGlu1β variant (Gu and Publicover 2000). With regard to group II mGlus, the expression of mGlu2 appears to be highly restricted to neurons only, whereas mGlu3 has been found in rat pinealocytes (Yamada et al. 1998), thymocytes (Storto et al. 2000b) and pancreatic islets (Brice et al. 2002). The presence and activity of group III mGlus has been demonstrated in rodent chondrocytes (Wang et al. 2005), cultured calvarial osteoblasts (Hinoi et al. 2001) and pancreatic islets (Brice et al. 2002; Tong et al. 2002; Uehara et al. 2004). In the pancreatic islets of Langherans, mGlu4 and mGlu8 have been proposed to contribute to the regulation of glucagone secretion by alpha cells (Tong et al. 2002; Uehara et al. 2004). In a recent study, bone marrow stromal cells have been shown to express functional mGlu6, which inhibits Ca2+ influx and nitric oxide synthase activity (Foreman et al. 2005), as have retinal rod bipolar cells, the only other site of expression of mGlu6 (Nakajima et al. 1993; Nomura et al. 1994). One of the most important findings associated with the expression of mGlus in peripheral tissues has been the ectopic expression of mGlu1 in melanomas (Marin and Chen 2004). The mouse mutant line TG3, in which multiple tandem insertions are present in the Grm1 locus with a concomitant deletion of 70 kb intronic DNA, has been found to be highly predisposed to develop melanoma (Pollock et al. 2003). Strong mGlu1α expression has been detected in melanomas derived from these mice and in several human melanoma biopsy samples and melanoma cell lines, but not in normal human or mouse melanocytes (Pollock et al. 2003; Marin and Chen 2004). Moreover, in a line of transgenic mice with mGlu1α expression targeted to melanocytes, severe development of melanoma has been observed (Pollock et al. 2003; Marin and Chen 2004). These findings strongly suggest an involvement of mGlu1 signalling in the pathogenesis of melanocytic neoplasia, including the activation of ERK1/2 and protein kinase C (PKC), which have also been implicated in melanoma onset (Marin et al. 2005).

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Developmental aspects of mGlu expression Numerous studies have shown a differential regulation of mGlu expression during CNS development (Shigemoto et al. 1992; Catania et al. 1994; Lopez-Bendito et al. 2001; Turman et al. 2001; Di Giorgi Gerevini et al. 2004; Lujan et al. 2005). Activation or changes in the expression of mGlus have been related to a variety of important ontogenetic events, such as neuronal migration and the formation of synaptic circuitry. The differentiation of cortical laminae during corticogenesis is accompanied by subtype-specific regulation of mGlu expression (Reid et al. 1996; Blue et al. 1997; Casabona et al. 1997; Furuta and Martin 1999). In cortical layer I, CajalRetzius cells, which secrete the extracellular protein reelin and play a pivotal role in radial migration and laminar organization, have been shown to contain functional mGlu1α (Martinez-Galan et al. 2001). Protein levels of mGlu1α are found to increase progressively during pre- and post-natal development (Shigemoto et al. 1992; Catania et al. 1994; van den Pol et al. 1994) in numerous brain areas including the neocortex and hippocampus (Lopez-Bendito et al. 2002). Conversely, mGlu5 increases perinatally, with a peak around the second postnatal week, and then decreases thereafter (Catania et al. 1994; Romano et al. 1996; Lopez-Bendito et al. 2002). Changes in mGlu5 expression have been associated with a gradual decline in mGlu5a and a rise in mGlu5b, with the latter isoform predominating in adulthood (Minakami et al. 1995; Romano et al. 1996). At the ultrastructural level, mGlu5 is preferentially found in unmyelinated axons and pyramidal cell dendrites in the first two postnatal weeks (Lopez-Bendito et al. 2002; Hubert and Smith 2004). As development proceeds, the number of mGlu5-immunolabelled unmyelinated axons is markedly reduced and the receptor becomes more widely distributed on dendritic spines (Lopez-Bendito et al. 2002; Hubert and Smith 2004); such a redistribution of the mGlu5 receptor has also been observed in the thalamus (Liu et al. 1998). Age-dependent expression of mGlu5 in pre-terminal axons suggests a role in axonguidance and synaptogenesis. In agreement with this hypothesis, the inhibition of group I mGlus in organotypic midbrain cultures prevents the development of nigrostriatal projections (Plenz and Kitai 1998). Furthermore, a role for mGlu5 in the regulation of neurite elaboration has been shown in vitro (Mion et al. 2001). Several studies have demonstrated enhanced group-ImGlu-mediated polyphosphoinositide hydrolysis at critical times for synaptogenesis and synapse consolidation during early postnatal development in various brain areas (Nicoletti et al. 1986a,b; Dudek and Bear 1989; Palmer et al. 1990). A critical role for mGlu1 in synapse elimination has been demonstrated in the developing cerebellum (Kano et al. 1997; Levenes et al. 1997). Synapse elimination is

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believed to be the final step in neural circuit formation by producing the necessary refinement of redundant connectivity formed during development. Activity-dependent synapse selection occurs in the cerebellar cortex for both types of excitatory inputs received by Purkinje cells: the climbing fibres, which originate in the inferior olive, and the parallel fibres, which are the axons of granule cells. Elimination of the supernumerary climbing fibres proceeds in parallel with other developmental events in the cerebellum, reaching eventually, by the end of the third postnatal week, the innervation of each Purkinje cell by only one climbing fibre. This one-to-one relationship is maintained throughout life. Persistent multiple climbing fibre innervation is one of the most important features observed in mGlu1-null mice, without apparent defects in parallel fibre-Purkinje cell synaptogenesis (Kano et al. 1997; Levenes et al. 1997), and in a number of mice deficient in signal transduction elements, which include Gαq (Offermanns et al. 1997), PLCβ4 (Kano et al. 1998) and PKCγ (Kano et al. 1995), downstream of mGlu1. Reinsertion of mGlu1α in the Purkinje cells only of mGlu1null mice is able to induce normal regression of multiple climbing fibre innervation (Ichise et al. 2000). Taken together, these results clearly demonstrate that the activation of mGlu1 and of its downstream intracellular signaling cascade plays a critical role in the maturation of the cerebellar cortex. Evidence for differential patterns of expression during postnatal development has also been provided for group II and III mGlus (Catania et al. 1994; Duvoisin et al. 1995; Meguro et al. 1999; Turman et al. 2001; Di Giorgi Gerevini et al. 2004). Among group II mGlus, mGlu2 is poorly expressed postnatally and increases in the first two weeks of life. On the other hand, mGlu3 is highly expressed at birth and declines in the following 2-3 weeks (Catania et al. 1994). Regionally specific regulation during postnatal development has been reported for mGlu7a (Bradley et al. 1998). In cortical regions (hippocampus, neocortex and olfactory cortex), mGlu7a levels are highest at postnatal day 7 (P7) and P14 and then decline in older rats. In contrast, mGlu7a levels are highest at P7 in the pons/medulla and cerebellum and decrease markedly between P7 and P14. Immunoreactivity for mGlu7a is exceptionally dense in fibre tracts in P7 animals compared with adults. Furthermore, the pattern of mGlu7a immunoreactivity observed in certain brain structures, including cerebellum, piriform cortex and hippocampus, appears significantly different between P7 and adult animals (Bradley et al. 1998). High levels of mGlu8 transcripts have been found in the mouse at embryonic day 16 but the expression of this receptor progressively declines during postnatal development (Duvoisin et al. 1995).

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Differential subcellular localization of mGlus relative to transmitter release sites The regional distribution of mRNA and immunoreactivity for group I mGlus appears to be highly correlated, thus reflecting that these mGlu proteins are mostly localized in somatodendritic domains of neurons, near the site of protein synthesis. On the other hand, group II mGlus are observed not only in somatodendritic, but also in axonal domains, whereas group III mGlus, except for mGlu6, are present mainly in the presynaptic active zone of axon terminals. The immunogold preembedding method has further revealed distinct patterns of mGlu distribution relative to neurotransmitter release sites. Immunoreactivity for group I mGlus is preferentially observed at the periphery of the postsynaptic densities of asymmetrical synapses (Fig. 3) in many brain regions, including the cerebellar cortex, hippocampus (Baude et al. 1993; Nusser et al. 1994; Lujan et al. 1996, 1997), dorsal lateral geniculate nucleus, lateral posterior nucleus (Vidnyanszky et al. 1996) and ventral posterior thalamic nucleus (Liu et al. 1998). In symmetrical γ-aminobutyric acid (GABA)ergic synapses in the monkey pallidum, however, a large population of immunogold

Fig. 3 Electron micrograph showing pre-embedding immunolabelling for mGlu1α on the dendritic shaft of an interneuron in the rat basolateral amygdala (At axon terminal, d dendrite). Immunogold/ silver particles accumulate (arrows) at the periphery of the postsynaptic density of an asymmetric synapse (arrowhead). Additional immunometal particles can be seen far from the synapse on the plasma membrane. Immunolabelling was obtained with a rabbit polyclonal antibody against mGlu1α (dilution 1:500; Diasorin). Bar 0.3 μm

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particles for mGlu1α and mGlu5 has been seen in the main body of the postsynaptic specializations (Hanson and Smith 1999). At the head of Purkinje cell spines in the rat cerebellar cortex, about half of the immunogold particles for mGlu1α have been localized perisynaptically, i.e. within a 60-nm annulus surrounding the edge of synapses, whereas the remaining particles are distributed extrasynaptically at more distant positions (Lujan et al. 1997). At the head of CA1 pyramidal neuron spines, about one fourth of the immunogold particles for mGlu5 are also observed preferentially at the periphery of the postsynaptic density of asymmetrical synapses (Lujan et al. 1996, 1997). The requirement of repetitive synaptic stimulation to detect the activation of group I mGlus (Batchelor et al. 1994; Congar et al. 1997; Fiorillo and Williams 1998) may reflect the extrasynaptic location of these receptors (Baude et al. 1993; Nusser et al. 1994). The perisynaptic position of group I mGlus is also consistent with the discovery of synapseassociating proteins (Tu et al. 1999) linking group I mGlus and NMDA receptors located in the postsynaptic density and of membrane-delimited modulation of NMDA currents by mGlu1/5 in cultured cortical neurons (Yu et al. 1997). In contrast with the perisynaptic localization of group I mGlus, mGlu2 had no close association with glutamatergic synapses, for example, in the cerebellar Golgi cell dendrites (Lujan et al. 1997) and occurs in clusters in extrasynaptic sites (Lujan et al. 1997). The other member of group II mGlus, viz. mGlu3, has been localized to postsynaptic membrane specializations and perisynaptic plasma membrane within 60 nm of the edge of asymmetrical synapses in the dentate molecular layer (Tamaru et al. 2001). Thus, mGlu3 has been suggested to be associated even more closely with glutamatergic synapses than group I mGlus, at least in the dentate gyrus. In presynaptic elements, group II and group III mGlus are distributed differentially relative to the release site (Shigemoto et al. 1997; Wada et al. 1998). Group III mGlus are mainly localized to the presynaptic active zone (Fig. 4), whereas group II mGlus are often observed in preterminal portions of axons, being remote from the release site (Fig. 5). The majority of mGlu2 and mGlu3 in cerebellar Golgi cell axons (Lujan et al. 1997) and corticostriatal axons (Tamaru et al. 2001), respectively, is found in extrasynaptic membrane and only 2%–4% of immunogold particles are detected in the presynaptic active zone. In contrast, the majority of mGlu4, mGlu7a, mGlu7b and mGlu8a is detected in the presynaptic active zone in both glutamatergic and GABAergic terminals in various brain regions (Shigemoto et al. 1996, 1997; Wada et al. 1998; Mateos et al. 1999; Somogyi et al. 2003; Kogo et al. 2004; Ferraguti et al. 2005). The segregation into distinct compartments of group II and group III mGlus may indicate different sources of glutamate activating these receptors and

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Fig. 4 Electron micrograph showing pre-embedding immunolabelling for mGlu8a on the dendritic shaft of an interneuron in the rat piriform cortex (At axon terminal, d dendrite). Immunogold/silver particles accumulate (arrows) at the presynaptic active zone of asymmetrical synapses. Immunolabelling was obtained with a guinea pig polyclonal antibody against mGlu8a (Wada et al. 1998). Bar 0.3 μm

different effector molecules coupled to these receptors. Group III mGlus may function as autoreceptors, whereas group II mGlus might be activated by the spillover of glutamate from distant synapses on the same or other presynaptic elements (Vogt and Nicoll 1999). In the cerebellar cortex of the rat, for example, mGlu2/3 on axonal domains of Golgi cells mediates heterosynaptic inhibition from the adjacent mossy fibre terminals to control the GABA release from the Golgi cell terminals (Ohishi et al. 1994; Mitchell and Silver 2000). Immunogold

Fig. 5 Electron micrograph showing pre-embedding immunolabelling for mGlu2/3 in the axon terminals in the hippocampal CA3 area (At axon terminal). Immunogold/silver particles are often scattered in extrasynaptic sites in axon terminals and preterminals, whereas few are found in the presynaptic active zone (arrow). Immunolabelling was obtained with a guinea pig polyclonal antibody against mGlu2/3 (Shigemoto et al. 1997). Bar 0.3 μm

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particles for mGlu3 have also been found in GABAergic projection fibres in the thalamus suggesting that heterosynaptic sources of glutamate activate these receptors (Tamaru et al. 2001). Group III mGlus are also present in some GABAergic terminals (Kinoshita et al. 1998; Bradley et al. 1999; Corti et al. 2002; Kogo et al. 2004; Ferraguti et al. 2005) indicating heterosynaptic interaction. Numerous functional studies have suggested the co-localization of mGlus not only in glutamatergic and GABAergic synapses, but also in presynaptic terminals releasing other neurotransmitters. Agonists at group II mGlus have been shown to increase the release of 5-hydroxytryptamine in the rat periacqueductal grey (Maione et al. 1998) and frontal cortex (Cartmell et al. 2000; Lee and Croucher 2003). The regulation of noradrenaline release in the hippocampus has recently been proposed to occur through a cooperative mechanism involving nicotinic acetycholine receptors and mGlu5 present on the same noradrenergic nerve terminals (Parodi et al. 2006). Furthermore, group II presynaptic receptors have been proposed to modulate striatal acetylcholine release (Marti et al. 2001; Pisani et al. 2002). However, none of these studies has been substantiated by direct evidence of the coexistence of mGlus on 5hydroxytryptamine- or acetylcholine-containing terminals. We show here by double-immunofluorescence the colocalization of mGlu8a in boutons immunopositive for the vesicular acetylcholine transporter in rat hippocampus (Fig. 6). The mechanisms of presynaptic inhibition by group II and group III include the suppression of presynaptic voltage-dependent calcium channels, the activation of presynaptic K+ channels and the direct inhibition of regulated exocytosis (for a review, see Anwyl 1999). Although similar effector mechanisms have been reported with agonists selective for group II and group III mGlus in heterologous expression systems, a functional difference corresponding to the distinct presynaptic localization of these receptors has been reported in the hippocampus (Capogna 2004). In addition, extensive convincing evidence for presynaptic inhibitory effects mediated by group I mGlus has been reported. However, at least some of these effects are mediated by retrograde signaling through the endocannabinoid system as shown in the cerebellum (Maejima et al. 2001; Galante and Diana 2004), medial nucleus of the trapezoid body (Kushmerick et al. 2004), striatum (Narushima et al. 2006) and hippocampus (Varma et al. 2001; Ohno-Shosaku et al. 2002).

mGlus-interacting proteins In the last few years, the C-terminal domain of many mGlus has been shown to interact physically with a variety of

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Fig. 6 Fluorescence images showing the coexistence of mGlu8a and the vesicular acetylcholine transporter (VAchT) in axon terminals decorating CA1 stratum oriens interneurons immunoreactive for the muscarinic acetylcholine receptor 2 (M2) in the rat hippocampus. Immunofluorescence for mGlu8a is shown in red (CY3), VAchT Immunofluorescence in green (Alexa 488) and M2 immunolabelling in blue (AMCA). Several boutons show co-localization for mGlu8a and VAchT immunoreactivity (arrows). Primary antibodies: polyclonal guinea pig anti-mGlu8a (diluted 1:500; Shigemoto et al. 1997;

Ferraguti et al. 2005), rat anti-M2 (diluted 1:250; Chemicon) and goat anti-VAchT (diluted 1:1000; Promega). Immunodetection of antigenprimary antibody complexes was revealed by using a mixture of secondary antibodies conjugated to various fluorochromes: donkey anti-G.Pig-CY3 (1:400; Jackson ImmunoResearch), donkey anti-goatAlexa 488 (1:1000; Molecular Probes), horse anti-mouse-biotin (1:100; Vector Laboratories) followed by streptavidin-AMCA (1:1000; Vector Laboratories). Bar 10 μm

cytoskeletal, scaffolding and signaling proteins and with integral membrane receptors. Increasing evidence is beginning to show the way in which these interacting proteins are responsible for the correct targeting of mGlus to specific sub-cellular compartments, functional recycling, coupling to effector proteins and modulation of intracellular signalling (for a review, see Fagni et al. 2004). The cytosolic Ctermini of group I mGlus (but not mGlu1β and 1d) possess consensus motifs involved in the binding to Homer proteins (Tu et al. 1998, 1999). The Homer family consists of several members, namely Homer1a, −1b, −1c, −2 and -3 (Brakeman et al. 1997; Kato et al. 1997, 1998; Tu et al. 1998), which, with the only exception of Homer1a, are characterized by a C-terminal coiled-coil domain that allows these proteins to assemble into homo- and heterooligomeric complexes (Kato et al. 1998; Tu et al. 1998). Homer proteins are further characterized by an enabled/ VASP homology (EVH)-like domain, which binds specifically to a prolin-rich sequence (PPxxF) present not only in

group I mGlu receptors but also in several other proteins including inorganic phosphate (IP3) receptors, ryanodine receptors, store-operated transient receptor channels (TRPC) and Shank (Xiao et al. 2000). Although Homer proteins can potentially interact with mGlu1α, mGlu5a and mGlu5b in vitro, distribution studies have shown regionand cell-specific distributions of these proteins and receptors in the rodent brain (Xiao et al. 1998). The mGlu1α receptor distribution overlaps with that of Homer3, whereas mGlu5 extensively co-localizes with Homer1b and 1c (Brakeman et al. 1997; Ango et al. 2000; Kammermeier et al. 2000). Homer multimers can associate with group I mGlus and IP3 receptors providing a structural link between these two molecules (Tu et al. 1998). Homers have also been shown to associate with Shank, a scaffold protein that takes part in a macromolecular complex that is located at the postsynaptic density and that includes PSD95, NMDA receptors and several signaling proteins such as CaMKII (Tu et al. 1999; Sheng 2001). All these findings

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indicate that, at glutamatergic synapses, Homer proteins are involved in the organization of postsynaptic signaling molecules in a functional unit, bridging group I mGlus, IP3 and ryanodine receptors to scaffolding molecules such as Shank, which in turn are associated with several different effectors, i.e. ionotropic glutamate receptors (Sheng 2001). Two binding sites for calmodulin have been identified within the intracellular tail of mGlu5 (Minakami et al. 1997). Several serine/threonine residues within these sites are targets for PKC phosphorylation, which can be suppressed by calmodulin interaction (Minakami et al. 1997). These sites are homologous to the C-terminus of mGlu1α suggesting a similar interaction of calmodulin and mGlu1α (Minakami et al. 1997; Ishikawa et al. 1999). The PDZ-domain-containing protein tamalin has also been demonstrated to interact with the C-terminus of group I mGlus (Kitano et al. 2002). Tamalin associates with cytohesins, and mGlu1α/tamalin/cytohesin-2 complexes have been immunoprecipitated from both rat brain tissues and cotransfected COS-7 cells (Kitano et al. 2002). Experiments performed with mutated forms of tamalin indicate that it plays a role in the regulation of group I mGlus trafficking (Kitano et al. 2002). Tamalin is characterized by several different protein-binding domains that allow its interaction with several proteins involved in intracellular signalling, trafficking or scaffolding functions (Kitano et al. 2003). Moreover, tamalin has been shown to possess an immunoreceptor tyrosine-based activation motif (ITAM) that upon phosphorylation allows association with the syk kinase (Hirose et al. 2004). The kinases c-src and fyn can phosphorylate both ITAM and syk, after their recruitment (Hirose et al. 2004). Co-immunoprecipitation experiments have shown that, in rat brain, mGlu1α is present in complexes containing tamalin, c-src, fyn, syk and the phosphatase SHP-2 (Hirose et al. 2004). However, the functional significance of these interactions remains unclear. The C-terminal tail of group I mGlu receptors display additional specific interactions with members of the mammalian seven in absentia homologs (Siah) family (Ishikawa et al. 1999). The amino acid residues Lys905Pro932 of mGlu1α interact directly with Siah-1A and with Ca2+/calmodulin in a competitive manner (Ishikawa et al. 1999). Siah proteins contain a RING finger domain suggesting that they might participate in targeting specific proteins for degradation to the proteasome (Lorick et al. 1999). When coexpressed with mGlu1α in superior cervical ganglion neurons, Siah-1A partially reduces the inhibition of N-type Ca2+ currents exerted by mGlu1α (Kammermeier and Ikeda 2001). Thus far, with respect to the group II mGlus, no interacting proteins have been identified for mGlu2, although its C-terminal domain has been shown to specify

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PKC-independent inhibition of N- and L-type Ca2+ channels in cerebellar granule cells (Perroy et al. 2001). A weak interaction between the C-terminus of mGlu3 and the protein interacting with C kinase 1 (PICK1) has been reported (Hirbec et al. 2002). All members of the group III mGlu subgroup have been shown to interact with PICK1 (Boudin et al. 2000; El Far et al. 2000; Dev et al. 2001). PICK1 can oligomerize by means of its coiled-coil domain and acts as an adaptor protein interacting with group III mGlus and PKC-α through its PDZ domain (Staudinger et al. 1997). Clustering of mGlu7 at presynaptic release sites appears largely dependent on PICK1 (Boudin et al. 2000), although this is probably insufficient to determine the highly specific localization and enrichment of this receptor in the CNS. Other receptor-protein interactions have been reported for group III mGlus, namely mGlu4-6 and mGlu7a, but not mGlu8a, with syntenin and the glutamate receptor-interacting protein (Hirbec et al. 2002). The C-terminal tail of mGlu7b has been shown to have additional binding partners, including the catalytic γ-subunit of protein phosphatase 1 and the actin-binding protein filamin-A (Enz 2002a,b). Filamin-A, a member of the α-actinin/ spectrin/dystrophin family of actin-binding proteins, induces the polymerization of actin filaments and the formation of the actin meshwork adjacent to the cell plasma membrane (Hartwig and Kwiatkowski 1991). The significance of the filamin-A interaction with mGlu7b may be related to a scaffolding function and the maintenance of macromolecular complexes at synapses.

Target-cell-specific segregation of group III mGlus One of the most peculiar findings regarding presynaptic mGlu localization is the target-cell-specific concentration of group III mGlus in the presynaptic active zone (Fig. 7; Shigemoto et al. 1996, 1997; Dalezios et al. 2002; Somogyi et al. 2003; Ferraguti et al. 2005). In the rat hippocampus, pyramidal cell axon terminals presynaptic to a particular subpopulation of GABAergic interneurons (e.g. somatostatin/mGlu1α-positive cells) have a much higher level of presynaptic mGlu7a than axon terminals making synapses with pyramidal cells and other types of interneurons. Synapses emanating from the same axon, even within the same terminals, exhibit distinct densities of mGlu7a, depending on the nature of the postsynaptic target (Shigemoto et al. 1996). The segregation of mGlu7a between two release sites of a single terminal implies that the coupling of the receptor to its effector molecules is spatially restricted and probably membrane-delimited in order to ensure the specificity of local regulation. A similar target-specific segregation has also been found for mGlu7a

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mGlus. Ferraguti et al. (2005) have recently shown that mGlu8-enriched boutons selectively innervate neurochemically distinct interneurons strongly immunopositive for muscarinic M2 or mGlu1 receptors in the CA1 stratum oriens of the hippocampus. One of the mGlu8-decorated and M2-immunopositive interneurons has been recorded from and labelled in vivo and has been revealed as a CA1 trilaminar cell with complex spike bursts during theta oscillations and strong discharge during sharp wave/ripple events. The postsynaptic interneuron type-specific expression of the high-efficacy presynaptic group III mGlus in both glutamatergic and GABAergic boutons predicts a role in adjusting the activity of the targeted interneurons depending on the level of the activity of the network.

References

Fig. 7 Target-cell-specific concentration of mGlu7a in the presynaptic active zone. Pre-embedding immunolabelling for mGlu7a is concentrated in the presynaptic active zone of axon terminals making synapses with the dendritic shaft (d) of interneurons but not with pyramidal cell spines (s) in the rat hippocampal CA1 area. Immunolabelling was obtained with a rabbit polyclonal antibody against mGlu7a (Shigemoto et al. 1996). Bar 0.3 μm

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