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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.
Show detailsEight metabotropic glutamate receptors that embody three functional classes have been identified
Metabotropic glutamate receptors (mGluRs) are so named because they are linked by G proteins to cytoplasmic enzymes (see [1] for review). To date, eight mGluRs have been cloned and named mGluR1 through mGluR8. The genes for these receptors appear to encode seven-membrane-spanning proteins, and like the ionotropic receptors, they possess an unusually large extracellular domain preceding the membranespanning segments. Metabotropic glutamate receptors have been grouped into three functional classes based on amino acid-sequence homology, agonist pharmacology and the signal-transduction pathways to which they are coupled (Fig. 15-1). Members of each class share ~70% sequence homology, with about 45% homology between classes. Alternatively spliced variants have been described for mGluR1, mGluR4, mGluR5 and mGluR7.
Glutamate itself activates all of the recombinant metabotropic glutamate receptors but with widely varying potencies, ranging from 2 nM, in the case of mGluR8, to 1,000 μM, in the case of mGluR7. Highly selective agonists for each of the three groups have been identified. l-Amino-4-phosphonobutyrate (l-AP4) is a selective agonist of group III; 2R,4R-4-aminopyrrolidine-2-4-dicarboxylate (APDC) is a highly selective and reasonably potent (400 nM) agonist for group II, whereas 3,5-dihydroxyphenylglycine appears to be a selective group I agonist. Some other phenylglycine derivatives are antagonists of metabotropic glutamate receptors, but highly group-selective antagonists have not yet been identified.
Metabotropic glutamate receptors are linked to diverse effector mechanisms
The classification of metabotropic glutamate receptors into three groups is further supported by a consideration of their signal-transduction mechanisms. Group I receptors stimulate phosphoinositide-specific phospholipase C (PI-PLC) activity and the release of Ca2+ from cytoplasmic stores (Figs. 15-1 and 15-2). The ability to increase intracellular Ca2+ levels differs between the members of this class and their splice variants, a property probably attributable to the different affinities each receptor has for the G protein. Activation of PI-PLC leads to the formation of not only inositol-1,4,5-trisphosphate (IP3) but also diacylglycerol (DAG), which in turn activates protein kinase C (PKC) (see Chap. 21). Activation of group II and probably group III receptors results in inhibition of adenylyl cyclase (Figs. 15-1 and 15-2). This response is blocked by pertussis toxin, indicating that a G protein of the Gi family probably is involved (see Chap. 22).
Postsynaptic metabotropic glutamate receptors modulate ion channel activity
Metabotropic glutamate receptors located on the postsynaptic membrane modulate a wide variety of ligand- and voltage-gated ion channels expressed on central neurons, as would be expected if receptor activation is coupled to multiple effector enzymes. Activation of all three classes of mGluRs inhibits L-type voltage-dependent Ca2+ channels, and both group I and group II receptors inhibit N-type Ca2+ channels (Box 23-1). Metabotropic glutamate receptors also decrease a high-threshold Ca2+ current in spiking neurons of Xenopus retina. Metabotropic receptor activation closes voltage-dependent, acetylcholine-sensitive and Ca2+-dependent K+ channels in certain neurons, leading to slow depolarization and consequent neuronal excitation. The exact mechanism of mGluR modulation of K+ currents is at present unclear. In cerebellar granule cells, stimulation of metabotropic glutamate receptors increases the activity of Ca2+ dependent and inwardly rectifying K+ channels, leading to a reduction in excitability.
A large number of ligand-gated channels also are modulated by metabotropic glutamate receptor activation, including AMPA and NMDA receptors as well as dopamine, GABAA and norepinephrine receptors. Whether activation of metabotropic glutamate receptors inhibits or potentiates a receptor depends on what component of the signal-transduction mechanism is targeted and often is tissue-specific. For example, in hippocampal pyramidal cells, mGluR activation potentiates currents through NMDA receptors. The effect is reduced by PKC inhibitors and may be caused by a reduction in the affinity of the NMDA channel for its blocking ion, Mg2+. In contrast, in cerebellar granule cells, metabotropic-glutamate receptor activation inhibits NMDA receptor-induced elevations of [Ca2+]i also by a mechanism thought to involve PKC.
Metabotropic receptors can mediate presynaptic inhibition
Immunohistochemical studies at both the light and electron microscopic level have firmly placed a number of mGluRs at the presynaptic terminals of central neurons. Activation of presynaptic metabotropic glutamate receptors blocks both excitatory glutamatergic and inhibitory GABAergic synaptic transmission in a variety of central structures. For example, mossy fiber-evoked excitatory postsynaptic potentials (EPSPs) onto CA3 hippocampal pyramidal neurons are blocked by activation of mGluR2, which is located on presynaptic granule cell terminals. In contrast, transmission at synapses between Schaffer collaterals and CA1 pyramidal cells is resistant to mGluR2 agonists but is blocked by l-AP4, suggesting activation of mGluR4 or mGluR7. The actual mechanism of how mGluR activation regulates synaptic transmission is unclear. However, because all three mGluR groups inhibit voltage-dependent Ca2+ channels, it seems highly probable that presynaptic Ca2+ channels are a target for mGluR modulation. This has been demonstrated directly in the presynaptic terminal of the calyx of Held, where mGluR agonists suppress a high voltage-activated P/Q-type Ca2+ conductance, thereby inhibiting transmitter release at this glutamatergic synapse [18].
Genetic knockouts provide clues to metabotropic glutamate receptor functions
The ability to ascertain the precise physiological functions of metabotropic glutamate receptors has been hampered, in part, by the lack of sufficiently potent and selective pharmacological agents. The use of alternative strategies for the study of mGluRs, therefore, is clearly warranted. To address this problem, several groups have used gene targeting to produce knockout mice (see Chap. 40) that are devoid of the mGluR subtype of interest. These experiments have strongly suggested a physiological role for a number of receptors. Establishment of specific neuronal connections in the mature nervous system occurs through a process by which redundant connections formed during development are eliminated. In the adult cerebellum, each Purkinje cell is innervated by a single climbing fiber (CF) that originates from the inferior olive of the medulla. This one-to-one relationship is preceded by a developmental stage in which each Purkinje cell is innervated by multiple CFs. Massive elimination of synapses formed by CFs occurs postnatally, and a monosynaptic relationship is established at around postnatal day 20. Mice lacking the mGluR1 gene show symptoms of cerebellar dysfunction, such as ataxic gait, intention tremor and dysmetria, and are impaired in motor coordination and motor learning [19]. These mutant mice are deficient in long-term depression (LTD) at CF—Purkinje cell synapses, a form of synaptic plasticity in the cerebellum thought to be a cellular basis for motor learning (see Chap. 50). In addition, innervation of multiple CFs onto a Purkinje cell persists into adulthood in mGluR1 mutant mice, suggesting that the precise sculpting of these synaptic connections requires activation of mGluR1 during development.
The strong expression of mGluR2 in dentate gyrus granule cells has suggested a role for these receptors in presynaptic regulation of transmission at the mossy fiber—CA3 pyramidal neuron synapses, as described above. In mice lacking the mGluR2 gene, basal synaptic transmission and paired-pulse facilitation at the hippocampal mossy fiber to CA3 pyramidal synapses were indistinguishable from wild-type responses. In contrast, presynaptic inhibition at mossy fiber synapses induced by the mGluR2 agonist DCG-IV was reduced markedly in mutant mice, confirming a role for mGluR2 in the presynaptic regulation of neurotransmission. Interestingly, this mGluR2 deficiency was without effect on the magnitude of long-term potentiation (LTP) induced at these synapses, but LTD was impaired significantly [20]. These data suggest that mGluR2 is not required for mossy fiber LTP but is essential for mossy fiber LTD. In a variety of CNS structures, including the hippocampus, olfactory tract, spinal cord and thalamus, activation of presynaptically located group III mGluRs by l-AP4 inhibits synaptic transmission. One member of this group, mGluR4, is preferentially expressed in the cerebellum and has a role in the presynaptic regulation of synaptic transmission. Targeted elimination of the mGluR4 gene reveals that mGluR4 is essential in providing a presynaptic mechanism for maintaining synaptic efficacy during repetitive activation and suggests that the presence of mGluR4 at the parallel fiber—Purkinje cell synapse is required for maintaining normal motor function [21].
- Eight metabotropic glutamate receptors that embody three functional classes have been identified
- Metabotropic glutamate receptors are linked to diverse effector mechanisms
- Postsynaptic metabotropic glutamate receptors modulate ion channel activity
- Metabotropic receptors can mediate presynaptic inhibition
- Genetic knockouts provide clues to metabotropic glutamate receptor functions
- Metabotropic Receptors Modulate Synaptic Transmission - Basic NeurochemistryMetabotropic Receptors Modulate Synaptic Transmission - Basic Neurochemistry
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