![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322
3To whom correspondence should be addressed.
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONGlutamate receptor molecular...Peripheral glutamate receptorsGlutamate receptors in taste...SUMMARYREFERENCES |
|---|
-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA),
N-methyl-D-aspartate (NMDA) and kainate
receptors. Fifteen functional subunits assemble together in
heteromultimeric complexes to form these receptors as follows:
GluR1–GluR4 for AMPA; GluR5–GluR7 and KA1-KA2 for kainate; and NR1,
NR2A-NR2D and NR3 for NMDA receptors. Within a subclass, the subunit
composition strongly influences the pharmacologic and biophysical
properties of the receptors. The metabotropic glutamate receptors fall
into the following three groups, each containing two or more individual
receptor proteins: group I (mGluR1, mGluR5), group II (mGluR2, mGluR3),
and group III (mGluR4, mGluR6, mGluR7 and mGluR8). In contrast to the
ionotropic receptors, the metabotropic glutamate receptors appear to
act as monomers or homodimers rather than heteromers. Messenger RNAs
encoding several ionotropic subunits and a mGluR4-like receptor have
been identified in taste buds. Although controversial, the evidence is
consistent with an NMDA receptor serving as a primary taste transducer
for monosodium glutamate (MSG), and a metabotropic glutamate receptor
modulating the flavor-enhancing effect of MSG. Thus the
neurotransmitter glutamate is intimately involved in the central
processing of taste information.
KEY WORDS: • taste receptor • -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid • N-methyl-D-aspartate • metabotropic • sensory transduction
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONGlutamate receptor molecular...Peripheral glutamate receptorsGlutamate receptors in taste...SUMMARYREFERENCES |
|---|
-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and
kainate. Calcium entry through certain glutamate receptor channels
plays important roles in development and in forms of synaptic
plasticity that may underlie higher order processes such as learning
and memory (Asztely and Gustafsson 1996
, Maren and Baudry 1995
). The effects of selective antagonists in
animal models have implicated both NMDA and
Ca2+-permeable AMPA receptors in a variety of
neurologic disorders that include epilepsy, ischemic brain damage, and,
more speculatively, neurodegenerative disorders such as Parkinson’s
and Alzheimer’s diseases, Huntington’s chorea and amyotrophic lateral
sclerosis. The GluR5 kainate receptor subunit is highly expressed in
primary sensory neurons that mediate pain sensation, and recent
evidence suggests that GluR5-selective antagonists can have analgesic
effects.
In contrast to the ionotropic glutamate receptors, the metabotropic
glutamate receptors (mGluR) are not ligand-gated cation channels
but are coupled to a variety of effector systems through
GTP-binding proteins (G proteins). Members of this more recently
discovered family of glutamate receptors are widespread throughout the
brain and play a variety of neuromodulatory roles [see Conn and Pin (1997)
, Pin and Duvoisin (1995)
for
reviews]. For example, mGluR are often localized presynaptically on
glutamatergic terminals where they can serve as autoreceptors involved
in regulating glutamate release. Presynaptic mGluR are also present on
-aminobutyric acid (GABA)ergic nerve terminals where they
serve as heteroceptors involved in reducing GABA release.
Postsynaptically localized mGluR often play an important role in
modulating neuronal excitability via regulation of voltage-gated
ion channels or in modulating the function of postsynaptic ionotropic
receptors. Metabotropic glutamate receptors are also present on glia
where they serve to regulate various glial functions, including
different forms of glial-neuronal signaling. A number of selective
mGluR agonists and antagonists have been developed that are being
considered for treatment of a variety of psychiatric and neurologic
conditions including anxiety disorders, epilepsy and chronic pain.
It is now well accepted that both ionotropic and metabotropic glutamate
receptors are essential components of synaptic transmission in the
mammalian brain. Several recent reviews of the molecular biology and
pharmacology of central glutamate receptors have appeared
(Ben-Ari et al. 1997
, Borges and Dingledine 1998
, Conn and Pin 1997
, Dingledine et al. 1999
, Myers et al. 1999
, Ozawa et al. 1998
, Pin and Duvoisin 1995
, Sucher et al. 1996
). In the remainder of this review, we will describe
briefly the molecular biology of the glutamate receptors, with special
emphasis on their potential roles in taste perception.
|
Glutamate receptor molecular biology |
|---|
|
TOPABSTRACTINTRODUCTIONGlutamate receptor molecular...Peripheral glutamate receptorsGlutamate receptors in taste...SUMMARYREFERENCES |
|---|
). These ionotropic receptor subunits coassemble with other subunits in
the same pharmacologic family to produce active receptors;
cross-assembly of subunits between receptor families apparently
does not occur, preserving a strict link between the molecular and
pharmacologic classifications. In addition, the 
1 and 2 genes are
distant structural relatives (18–25% amino acid identity;
Lomeli et al. 1993
), which do not form functional
channels by themselves, nor have they been shown to modify the function
of other subunit combinations. Genetic deletion of the 2 gene,
however, leads to loss of activity-related depression of the
parallel fiber-Purkinje cell synapse (Kashiwabuchi et al. 1995
); the mouse Lurcher neurological mutant was shown recently
to be caused by a gain-of-function mutation in 2, which leads to a
large constitutive inward current that may provide a genetic model for
excitotoxicity (Zuo et al. 1997
). Findings from genetic
deletion strategies have also suggested that the NR3A subunit may serve
a regulatory function in NMDA receptors (Das et al. 1998
).
|
, Hollmann et al. 1994
,
Kuner et al. 1996
, Wo and Oswald 1994
,
Wood et al. 1995
). Residues in this reentrant second
membrane loop control key permeation properties of the ion channel,
including the degree of Ca2+ permeability and
sensitivity to certain open channel blockers [e.g., Herlitze et al. (1993)
, Hume et al. (1991)
].
To date, eight distinct metabotropic glutamate receptor subtypes
(termed mGluR1–GluR8) have been identified by molecular cloning
(Conn and Pin 1997
, Pin and Duvoisin 1995
). Members of this receptor family bear no primary sequence
homology with ionotropic glutamate receptors or with the other major
families of G protein–coupled receptors. However, hydropathy plots
suggest that the membrane topology of mGluR may be similar to that of
other G protein–coupled receptors, with seven membrane-spanning
regions and an intracellular C-terminal tail. Also in common with
other G protein–coupled receptors, mGluR likely exist as monomers or
homodimers (Romano et al. 1996
) rather than as
heteromultimeric proteins. Despite these similarities, there are clear
differences between mGluR and other G protein–coupled receptors with
regard to the functional roles of different receptor domains. For
example, the ligand-binding domain of mGluR lies within the
extracellular N-terminal portion of the receptor rather than
involving the transmembrane-spanning regions. Also, the second
intracellular loop and the carboxy tail region appear to be critical
for coupling of mGluR to G proteins, rather than the third
intracellular loop.
The eight metabotropic glutamate receptor subtypes have been classified
into three major groups (Table 2
) on the basis of their sequence homology, pharmacologic characteristics
and second-messenger coupling (Conn and Pin 1997
,
Pin and Duvoisin 1995
). Group I receptors consist of
mGluR1, mGluR5 and their splice variants, and couple to the activation
of phospholipase C and the hydrolysis of membrane phosphoinositides
in a variety of expression systems. Group II mGluR include mGluR2 and
mGluR3, which couple negatively to adenylyl cyclase in expression
systems. Group III consists of mGluR4, mGluR6, mGluR7 and mGluR8, which
also couple negatively to adenylyl cyclase in expression systems
(Conn and Pin 1997
). Members of each group show >60%
homology with other members of the same group and ~40% homology with
members of different groups. In native preparations, such as brain
slices and primary cell cultures, mGluR exhibit coupling to the same
signal transduction systems as shown in expression systems (Conn and Pin 1997
). In addition, mGluR have been shown to activate
other effector systems through a variety of direct or indirect
mechanisms. These include activation of phospholipase D (Boss et al. 1994
, Holler et al. 1993
), potentiation of
cyclic AMP responses to activation of Gs-coupled
receptors (Alexander et al. 1992
, Winder and Conn 1993
), increases in cyclic GMP levels (Okada 1992
), activation of phospholipase A2 and release
of arachidonic acid (Dumuis et al. 1993
, Stella et al. 1994
).
|
|
Peripheral glutamate receptors |
|---|
|
TOPABSTRACTINTRODUCTIONGlutamate receptor molecular...Peripheral glutamate receptorsGlutamate receptors in taste...SUMMARYREFERENCES |
|---|
, Weaver et al. 1996
), and osteoclasts and osteoblasts express NMDA receptors
(Chenu et al. 1998
, Patton et al. 1998
).
Furthermore, selective metabotropic glutamate receptor agonists induce
phosphoinositide hydrolysis in primary cultures of rat hepatocytes
(Copani et al. 1997). The functional roles of
these peripheral glutamate receptors raise the possibility that
antagonists restricted to the periphery might find uses in the
treatment of disorders such as diabetes and osteoporosis. Moreover,
NMDA and non-NMDA receptors are present in small, unmyelinated
sensory nerve terminals in the skin (Ault and Hildebrand, 1993
, Carlton et al. 1995
). NMDA receptor
antagonists can also reduce histamine secretion from mast cells
collected from the rat peritoneal cavity (Purcell et al. 1996
), although the molecular identity of the NMDA receptors
responsible has not been reported. Thus the potential therapeutic realm
of drugs targeted to ionotropic and possibly metabotropic glutamate
receptors is expanding to include cells (neural and nonneural) in the
periphery. In all cases examined, the peripheral NMDA receptors appear to be comprised of the NR1 and NR2D subunits only. The NR2D subunit, which is relatively scarce in the adult brain, confers a small single-channel conductance, weak desensitization and slow deactivation, resulting in small, prolonged responses of NMDA receptors.
|
Glutamate receptors in taste buds |
|---|
|
TOPABSTRACTINTRODUCTIONGlutamate receptor molecular...Peripheral glutamate receptorsGlutamate receptors in taste...SUMMARYREFERENCES |
|---|
). However, available
evidence suggests that either an NMDA or mGluR4-like receptor may
mediate the flavor-enhancing effects of monosodium glutamate (MSG),
as described below.
The membrane transduction mechanisms responsible for the "umami"
primary taste sensation triggered by MSG have been studied in acutely
isolated taste receptor cells by several groups. In most rat taste
receptor cells dissociated from taste buds, high concentrations of
L-amino-4-phosphonobutyrate (L-AP4; 0.83
mmol/L) and glutamate (10–20 mmol/L) could be shown to close
nonspecific cation channels, giving rise to a very small (6 pA for
glutamate, 2 pA for L-AP4) sustained outward current
(Bigiani et al. 1997
). It is important to recognize that
these high agonist concentrations are also required for the MSG taste
sensation. Whether these very small hyperpolarizing currents could be
responsible for taste transduction is doubtful, but they might serve to
modulate transduction mediated by another receptor. Much less
frequently, glutamate also caused transient opening of nonselective
cation channels (Bigiani et al. 1997
), producing
somewhat larger (>20 pA at -85 mV) transient inward currents that
desensitized slowly over 20–30 s. The receptor mediating this
depolarizing glutamate response was not characterized, but no
depolarizing L-AP4 currents were found. In a different
study, Hayashi et al. (1996)
recorded signals from
clusters of about a dozen taste cells in isolated taste bud fragments
from mouse tongue that had been loaded with both
Ca2+-sensitive and voltage-sensitive dyes. In
their experiments NMDA (1 mmol/L) depolarized taste cells with an
accompanying rise in
[Ca2+]i, whereas
depolarization caused by L-AP4 (1 mmol/L) was accompanied
by a decline in resting
[Ca2+]i. Glutamate (1
mmol/L) depolarized only taste cells but caused both increases and
decreases of [Ca2+]i in
different cells. taken together, these observations suggest the
presence of functional ionotropic (NMDA) as well as metabotropic
receptors in mouse taste buds. However, it will be essential to confirm
the identity of the functional receptors with antagonists.
Evidence from reverse transcriptase-polymerase chain reaction
(RT-PCR) and in situ hybridization indicates that the mGluR4
metabotropic glutamate receptor, or a very closely related protein, is
expressed in vallate and foliate taste buds (Chaudhari et al. 1996
). Recombinant mGluR4 can be activated by glutamate and
L-AP4 with 50% effective concentrations
(EC50) of 10 and 1 µmol/L,
respectively (Conn and Pin 1997
). The need for much
higher agonist concentrations to activate taste cell receptors suggests
that a new mGluR4 splice variant or, less likely, an entirely new gene
product related to mGluR4, may be expressed by taste cells. RT-PCR
also provided evidence for the presence of NR1, NR2D and KA2 mRNAs in
tongue epithelium (Chaudhari et al. 1996
), but in situ
hybridization indicates that these ionotropic receptor subunits are
expressed by taste cells as well as other cells. Thus, in contrast to
the selective localization of mGluR4 to taste cells, the NMDA receptor
subunits are expressed by several cell types in the tongue.
To explore further the potential role of mGluR4 in taste sensation,
Roper et al. (1997)
studied taste preferences in mice
lacking the mGluR4 gene. The "sweet" and "salty" taste
preference in mGluR4 knockout mice was unaltered compared with
wild-type controls, but the knockout mice showed a much stronger
preference for MSG. This result is consistent with the predominantly
hyperpolarizing effect of L-AP4 (Bigiani et al. 1997
), which serves to suppress taste sensations.
|
SUMMARY |
|---|
|
TOPABSTRACTINTRODUCTIONGlutamate receptor molecular...Peripheral glutamate receptorsGlutamate receptors in taste...SUMMARYREFERENCES |
|---|
and 1998
), the mechanisms underlying
glutamate taste transduction should continue to receive attention.
|
FOOTNOTES |
|---|
2 Supported by the National Institutes of Health.
4 Abbreviations used: AMPA, -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid;
L-AP4, L-amino-4-phosphonobutyrate; GABA, -aminobutyric acid; mGluR, metabotropic glutamate receptors; MSG, monosodium glutamate; NMDA, N-methyl-D-aspartate; RT-PCR, reverse
transcriptase-polymerase chain reaction.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONGlutamate receptor molecular...Peripheral glutamate receptorsGlutamate receptors in taste...SUMMARYREFERENCES |
|---|
1. Alexander S.P.H., Curtis A. R., Hill S. J., Kendall D. A. Activation of a metabotropic excitatory amino acid receptor potentiates A2b adenosine receptor-stimulated cyclic AMP accumulation. Neurosci. Lett. 1992;146:231-233[Medline]
2. Asztely F., Gustafsson B. Ionotropic glutamate receptors: their role in the expression of hippocampal synaptic plasticity. Mol. Neurobiol. 1996;12:1-11[Medline]
3.
Ault B., Hildebrand L. M. Activation of nociceptive reflexes by peripheral kainate receptors. J. Pharmacol. Exp. Ther. 1993;265:927-932
4. Ben-Ari Y., Khazipov R., Leinekugel X., Caillard O., Gaiarsa J. L. GABAA, NMDA and AMPA receptors: a developmentally regulated "menage à trois.". Trends Neurosci. 1997;20:523-529[Medline]
5. Bennett J. A., Dingledine R. Topology profile for a glutamate receptor: three transmembrane domains and a channel-lining reentrant membrane loop. Neuron 1995;14:373-384[Medline]
6.
Bigiani A., Delay R. J., Chaudhari N., Kinnamon S. C., Roper S. D. Responses to glutamate in rat taste cells. J. Neurophysiol. 1997;77:3048-3059
7. Borges K., Dingledine R. AMPA receptors: molecular and functional diversity. Prog. Brain Res. 1998;116:140-157
8. Boss V., Nutt K. M., Conn P. J. L-Cysteine sulfinic acid as an endogenous agonist of a novel metabotropic receptor coupled to stimulation of phospholipase D activity. Mol. Pharmacol. 1994;45:1177-1182[Abstract]
9. Carlton S. M., Hargett G. L., Coggeshall R. E. Localization and activation of glutamate receptors in unmyelinated axons of rat glabrous skin. Neurosci. Lett. 1995;197:25-28[Medline]
10.
Chaudhari N., Yang H., Lamp C., Delay E., Cartford C., Than T., Roper S. The taste of monosodium glutamate: membrane receptors in taste buds. J. Neurosci. 1996;16:3817-3826
11. Chenu C., Serre C. M., Raynal C., Burt-Pichat B., Delmas P. D. Glutamate receptors are expressed by bone cells and are involved in bone resorption. Bone 1998;22:295-299[Medline]
12. Conn P. J., Pin J.-P. Metabotropic glutamate receptors. Annu. Rev. Pharmacol. Toxicol. 1997;37:205-238[Medline]
13. Das S., Sasaki Y. F., Rothe T., Premkumar L. S., Takasu M., Crandall J. E., Dikkes P., Conner D. A., Rayudu P. V., Cheung W., Vincent Chen H.-S., Lipton S. A., Nakanishi N. Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A. Nature (Lond.) 1998;393:377-381[Medline]
14.
Dingledine R., Borges K., Bowie D., Traynelis S. F. The glutamate receptor ion channels. Pharmacol. Rev. 1999;51:7-61
15. Dumuis A., Sebben M., Fagni L., Prezeau L., Manzoni O., Cragoe E. J., Jr, Bockaert J. Stimulation by glutamate receptors of arachidonic acid release depends on the Na+/Ca2+ exchanger in neuronal cells. Mol. Pharmacol. 1993;43:976-981[Abstract]
16. Hayashi Y., Zviman M. M., Brand J. G., Teeter J. H., Restrepo D. Measurement of membrane potential and [Ca2+]i in cell ensembles: application to the study of glutamate taste in mice. Biophys. J. 1996;71:1057-1070[Medline]
17. Herlitze S., Raditsch M., Ruppersberg J. P., Jahn W., Monyer H., Schoepfer R., Witzemann V. Argiotoxin detects molecular differences in AMPA receptor channels. Neuron 1993;10:1131-1140[Medline]
18. Holler T., Cappel E., Klein J., Loffelholz K. Glutamate activates phospholipase D in hippocampal slices of newborn and adult rats. J. Neurochem. 1993;61:1569-1572[Medline]
19. Hollmann M., Maron C., Heinemann S. N-Glycosylation site tagging suggests a three transmembrane domain topology for the glutamate receptor GluR1. Neuron 1994;13:1331-1343[Medline]
20.
Hume R. I., Dingledine R., Heinemann S. F. Identification of a site in glutamate receptor subunits that controls calcium permeability. Science (Washington DC) 1991;253:1028-1031
21. Inagaki N., Kuromi H., Gonoi T., Okamoto Y., Ishida H., Seino Y., Kaneko T., Iwanaga T., Seino S. Expression and role of ionotropic glutamate receptors in pancreatic islet cells. FASEB J 1995;9:686-691[Abstract]
22. Kashiwabuchi N., Ikeda K., Araki K., Hirano T., Shibuki K., Takayama C., Inoue Y., Kutsuwada T., Yagi T., Kang Y., Aizawa S., Mishina M. Impairment of motor coordination, Purkinje cell synapse formation, and cerebellar long-term depression in GluR mutant mice. Cell 1995;81:245-252[Medline]
23. Kinnamon S. C., Margolskee R. F. Mechanisms of taste transduction. Curr. Opin. Neurobiol. 1996;6:506-513[Medline]
24. Kuner T., Wollmuth L. P., Karlin A., Seeburg P. H., Sakmann B. Structure of the NMDA receptor channel M2 segment inferred from the accessibility of cysteines. Neuron 1996;17:343-352[Medline]
25. Lomeli H., Sprengel R., Laurie D. J., Kohr G., Herb A., Seeburg P. H., Wisden W. The rat delta-1 and delta-2 subunits extend the excitatory amino acid receptor family. FEBS Lett 1993;315:318-322[Medline]
26. Maren S., Baudry M. Properties and mechanisms of long-term synaptic plasticity in the mammalian brain: relationships to learning and memory. Neurobiol. Learn. Mem. 1995;63:1-18[Medline]
27. Myers S. J., Dingledine R., Borges K. Genetic regulation of glutamate receptors. Annu. Rev. Pharmacol. Toxicol. 1999;39:221-241[Medline]
28. Okada D. Two pathways of cyclic GMP production through glutamate receptor-mediated nitric oxide synthesis. J. Neurochem. 1992;59:1203-1210[Medline]
29. Ozawa S., Kamiya H., Tsuzuki K. Glutamate receptors in the mammalian central nervous system. Prog. Neurobiol. 1998;54:581-618[Medline]
30. Patton A. J., Genever P. G., Birch M. A., Suva L. J., Skerry T. M. Expression of an N-methyl-D-aspartate-type receptor by human and rat osteoblasts and osteoclasts suggests a novel glutamate signaling pathway in bone. Bone 1998;22:645-649[Medline]
31. Pin J.-P., Duvoisin R. Neurotransmitter receptors I: The metabotropic glutamate receptors: structure and functions. Neuropharmacology 1995;34:1-26[Medline]
32. Purcell W. M., Doyle K. M., Westgate C., Atterwill C. K. Characterization of a functional polyamine site on rat mast cells: association with a NMDA receptor macrocomplex. J. Neuroimmunol. 1996;65:49-53[Medline]
33.
Romano C., Yang W. L., O’Malley K. L. Metabotropic glutamate receptor 5 is a disulfide-linked dimer. J. Biol. Chem. 1996;271:28612-28616
34. Roper S. D., Hampson D. R., Chaudhari N. Mice lacking the metabotropic glutamate receptor 4 show altered taste preference. Soc. Neurosci. Abst. 1997;23:1037(abs.)
35.
Schiffman S. S. Taste and smell losses in normal aging and disease. J. Am. Med. Assoc. 1997;278:1357-1362
36. Schiffman S. S. Sensory enhancement of foods for the elderly with monosodium glutamate and flavors. Food Rev. Int. 1998;14:321-333
37. Stella N., Tencé M., Glowinski J., Prémont J. Glutamate-evoked release of arachidonic acid from mouse brain astrocytes. J. Neurosci. 1994;14:568-575[Abstract]
38. Sucher N. J., Awobuluyi M., Choi Y. B., Lipton S. A. NMDA receptors: from genes to channels. Trends Pharmacol. Sci. 1996;17:348-355[Medline]
39.
Weaver C. D., Yao T. L., Powers A. C., Verdoorn T. A. Differential expression of glutamate receptor subtypes in rat pancreatic islets. J. Biol. Chem. 1996;271:12977-12984
40. Winder D. G., Conn P. J. Activation of metabotropic glutamate receptors increases cAMP accumulation in hippocampus by potentiating responses to endogenous adenosine. J. Neurosci. 1993;13:38-44[Abstract]
41.
Wo Z. G., Oswald R. E. Transmembrane topology of two kainate receptor subunits revealed by N-glycosylation. Proc. Natl. Acad. Sci. U.S.A. 1994;91:7154-7158
42.
Wood M. W., VanDongen H.M.A., VanDongen A.M.J. Structural conservation of ion conduction pathways in K channel and glutamate receptors. Proc. Natl. Acad. Sci. U.S.A. 1995;92:4882-4886
43.
Zuo J., DeJager P. L., Takahashi K. A., Jiang W., Linden D. J., Heintz N. Neurodegeneration in Lurcher mice caused by mutation in 2 glutamate receptor gene. Nature (Lond.) 1997;388:769-773[Medline]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
