![[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}
|
|
|
|
|
||
Monell Chemical Senses Center, Veterans Affairs Medical Center, Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONInteraction of glutamate with...Transduction models for umami...SUMMARYREFERENCES |
|---|
KEY WORDS: • umami • glutamate • taste • nucleotides • calcium imaging • glutamate receptor
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONInteraction of glutamate with...Transduction models for umami...SUMMARYREFERENCES |
|---|
, Kawamura et al. 1991
,
Yamaguchi 1998
). Whether a taste can be described as
primary depends on a number of mutable criteria. Such criteria may
include the following: 1) psychophysical and descriptive
data that tend to isolate one primary taste from another on the basis
of statistical criteria; 2) electrophysiologic evidence that
reports unique neural transduction features of the putative taste
modality; and 3) biochemical and molecular biological
evidence that identifies and localizes unique receptors and cellular
responses to the candidate primary modality. These criteria have
generally been fulfilled for the modalities of sweet, sour, salty and
bitter (Brand 1997
), and parallel studies are now
meeting these criteria for umami as well. The criterion involving
unique receptor processes has seen much support within the past few
years. The fact that the major prototypical stimulus for umami taste is
the sodium salt of L-glutamic acid raises the hypothesis
that the receptor(s) for this modality may be related to one or more of
the many known receptor types for glutamate found in the central
nervous system
(CNS)3
(Faurion 1991
, Hollmann and Heinemann 1994
, Monaghan and Wenthold 1997
, Pin and Bockaert 1995
).
A variety of CNS neurotransmitter receptors for glutamate have been
identified (Conn and Patel 1994
, Hollmann and Heinemann 1994
, Monaghan and Wenthold 1997
).
These may generally be placed into two structural categories, i.e.,
stimulus-gated ion channels and the metabotropic receptors. The
ionotropic receptors induce signal transduction by altering ion flux
through an ion channel directly coupled to and gated by a glutamate
binding site. Metabotropic receptors are G protein–linked receptors in
which glutamate binding induces changes in intracellular messengers
that then alter the balance of intracellular ions. Studies of the taste
receptor for glutamate should, like their counterpoints of the CNS,
strive to make use of any unique pharmacology of these
glutamate-responsive systems. For example, most of the glutamate
receptor types in the CNS are distinguishable through their specificity
toward certain agonists and antagonists. Thus, of the ionotropic
glutamate receptors, classes can be delineated roughly by their
differential sensitivity to glutamate analogs such as
-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA), kainic acid
and N-methyl-D-aspartate (NMDA)
(Hollmann and Heinemann 1994
).
It is appropriate to determine the agonist/antagonist responses of
glutamate taste receptors as well, allowing inferences to be made as to
the type of receptors involved with umami taste. In addition, the
unique properties of a putative umami receptor should be reflected in
the response and pharmacology of that receptor. In taste, for example,
certain 5'-ribonucleotides can enhance the intensity of the taste of
the sodium salt of L-glutamate (MSG) in a true taste
synergy (Rifkin and Bartoshuk 1980
, Yamaguchi 1967
, Yamaguchi et al. 1971
). The umami taste
receptor is also less sensitive to glutamate than are most of the CNS
glutamate receptors, with the taste response appearing in the
millimolar concentration range for glutamate. Successful
characterization of the umami taste receptor must therefore include a
functional explanation for this synergy and match the sensitivity of
the receptor to the known psychophysics of umami taste.
This review will examine previous biochemical and biophysical studies documenting the probable existence of a putative umami taste receptor. It will also attempt to integrate these observations into a working hypothesis to describe the receptor processes for umami taste.
|
Interaction of glutamate with receptor sites |
|---|
|
TOPABSTRACTINTRODUCTIONInteraction of glutamate with...Transduction models for umami...SUMMARYREFERENCES |
|---|
demonstrated that MSG imparted a taste to the
Slc:ICR strain of mouse that is different from those conferred by
sweet, sour, salty and bitter stimuli. They also showed that certain
fibers of the glossopharyngeal (CN IX) of the mouse were uniquely
sensitive to MSG and that these fibers displayed a synergistic response
to MSG plus guanosine-5'-monophosphate (GMP) (Ninomiya and Funakoshi 1989b
). These data indicate that this strain of mouse
can discriminate MSG from other basic tastes and that this
discrimination is based primarily on information carried from the
periphery by fibers of CN IX. Equally convincing were studies in dogs
from Kurihara’s laboratory (Kumazawa and Kurihara 1990
,
Kumazawa et al. 1991
). The data show, interestingly,
that not every dog responded to 5'-ribonucleotides and that sensitivity
to MSG varied. In dogs, contrary to mice, chorda tympani nerve (CN VII)
recordings could be used to demonstrate a synergism between MSG and MSG
plus inosine-5'-monophosphate (IMP), GMP or AMP; (AMP was effective
only in beagle dogs). Similar responses to MSG have been found in
primates. In chimpanzees, MSG tended to stimulate a subpopulation of
chorda tympani fibers (Hellekant et al. 1997
), whereas
further into the CNS, separate representations for umami stimuli were
localized into the orbitofrontal cortex (Rolls 1997
).
Many other studies with rodents and primates support the hypothesis to
varying degrees [see discussion in Kumazawa et al. (1991)
]. One main observation from these studies was the
species, and even strain and individual variation, shown in response
to stimulation by MSG and the synergism with the
5'-ribonucleotides. Great care must be taken, therefore, in
generalizing effects from one species to another.
The first biochemical studies to characterize the receptor for
glutamate in taste tissue reported that L-glutamate bound
in a tissue-specific manner to a partial membrane preparation from
bovine circumvallate taste tissue. This binding could be enhanced by
the presence of certain 5'-ribonucleotides (Torii and Cagan 1980
). Results of this study reflected the expected criteria
for a taste-glutamate receptor, in that the binding was weak
(Kd of 20–30 mmol/L), and the synergism was
demonstrable as an increase in binding of glutamate to the tissue
preparation. Kinetic evaluation of the binding data with and without
the 5'-ribonucleotide, GMP, suggested that GMP increased the number of
binding sites for L-glutamate, yet did not significantly
change the affinity of the receptor for glutamate. In addition, not
every 5'-ribonucleotide evaluated demonstrated a synergism. In this
tissue, IMP-, GMP- and uridine 5'-monophosphate (UMP)-enhanced binding
of L-glutamate, whereas xanthosine 5'-monophosphate (XMP),
cytosine 5'-monophosphate (CMP) and adenosine 5'-monophosphate (AMP)
did not.
The neural and biochemical data both suggested an
allosteric-type model for MSG/5'-ribonucleotide binding
interaction (Cagan 1987
, Kumazawa et al. 1991
). The biochemical binding data suggested that active
5'-ribonucleotides caused an increase in the number of binding sites
for L-glutamate (Torii and Cagan 1980
),
whereas Kurihara’s model emphasized a likely increase in affinity for
L-glutamate as a result of nucleotide interaction with a
closely associated site (Kumazawa et al. 1991
). Whatever
the nature of the synergism, it is evident from these early reports
that biochemical and neurophysiologic studies point to specific
peripheral receptor processes for umami taste.
|
Transduction models for umami taste |
|---|
|
TOPABSTRACTINTRODUCTIONInteraction of glutamate with...Transduction models for umami...SUMMARYREFERENCES |
|---|
, Teeter et al. 1992
). This conductance increase was graded with glutamate
concentration, was distinct from any sodium-induced currents and
could be enhanced by the addition of 5'-GMP, a known enhancer of the
glutamate response in this mouse strain. These findings suggested that
the taste receptor for glutamate in the mouse may be of the
stimulus-gated ion channel type, perhaps similar to an
NMDA-type glutamate receptor channel.
Subsequent studies have used imaging dyes to monitor both intracellular
calcium and membrane voltage in isolated taste cells from mouse (C3H)
vallate and foliate taste tissue (Hayashi et al. 1996
and 1997
). These cells responded to L-glutamate with
either increases or decreases in intracellular calcium (Fig. 1A
). Membrane depolarization was generally accompanied by increases in
intracellular calcium, suggesting an inward current. The glutamate
analog, L-2-amino-4-phosphonobutyrate (L-AP4),
a stimulator of metabotropic glutamate receptors, elicited primarily
decreases in intracellular calcium, accompanied by little or no change
in membrane depolarization (Fig. 1B
). The analog, NMDA,
elicited only increases in intracellular calcium, accompanied by a
depolarization (Fig. 1C
). L-Glutamate (1 mmol/L)
plus GMP (1 mmol/L) elicited primarily increases in intracellular
calcium. These data suggest, therefore, that there may be at least two
types of glutamate receptors in taste cells, i.e., one an excitatory
receptor, likely similar to a stimulus-gated ion channel NMDA type,
and another of the metabotropic type, which may be primarily an
inhibitory signal.
|
. Their studies reported that a
cDNA library, constructed from rat vallate tissue, included sequences
similar to known CNS glutamate receptors. Several clones were found,
including ones that coded for NMDA-type receptors. In situ
hybridization studies showed that one of these, a low abundance clone
for a metabotropic receptor of the mGluR4 family, could be localized
specifically to the taste buds of rat vallate. A conditioned taste
aversion study in rats found that L-AP4 generalized to MSG,
whereas NMDA did not, suggesting that to the rat, L-AP4
tasted like MSG. Imaging and patch recordings of isolated taste cells
using the stimulus, L-AP4, an agonist of the mGluR4 family,
supported the finding that this type of glutamate receptor is present
in the taste system. Patch recordings from taste cells of rat vallate
indicated that in most cells studied, glutamate (and L-AP4)
induced an outward current, whereas in a small number of other cells,
glutamate induced a transient inward current (Bigiani et al. 1997
). It is apparent that both hypotheses are tenable. Both NMDA-type and mGluR receptors are present on the membranes of taste cells. Yet, like their counterparts in the CNS, both lead to opposite transductional responses. How are these excitatory and inhibitory signals integrated within the taste bud so that an excitatory signal is sent to the CNS?
|
SUMMARY |
|---|
|
TOPABSTRACTINTRODUCTIONInteraction of glutamate with...Transduction models for umami...SUMMARYREFERENCES |
|---|
). It is also possible that the metabotropic receptor functions in taste
transduction because inhibitory responses could be important in taste
processing, particularly at the level of the taste bud. The mGluR4
receptor is one that alters levels of intracellular messengers, in this
case, causing decreases in cAMP by inhibiting the action of adenyly
cyclase. A Gi/o-type G protein is likely involved
(Fig. 2B
).
|
), which, as in the visual
system, then transforms the initial inhibitory signal into an
excitatory one. It is also possible that the actual umami receptor is
one of a subset of metabotropic receptors for glutamate whose
properties are not yet explored because its low abundance has not yet
allowed excitatory responses to be observed. The receptor and transduction processes for umami are just beginning to be explored. Future studies will clone an NMDA-type receptor in taste cells, and single cell polymerase chain reaction can be used to determine whether more than one type of receptor is expressed in a single taste cell. Until now, all reported single taste cell biophysical responses have shown cell segregation of mGluR- and NMDA-type receptors. But the question of multiple receptors on a given cell remains open. In addition, more pharmacologic studies must be carried out with the 5'-ribonucleotides to explain both their stimulatory and synergistic responses in umami taste. These biophysical and molecular studies will then be integrated with on-going psychophysical and neural studies to provide a coherent explanation of umami taste transduction.
|
ACKNOWLEDGMENTS |
|---|
Note Added in Proof: Recently published studies have further clarified the likely dual role for metabotropic and ionotropic mechanisms for umami taste. Using isolated taste bud cells from rat fungiform, Lin and Kinnamon (J. Neurophysiol. 82: 2061–2069, 1999) show three types of glutamate induced responses: one being a depolarizing NMDA-type, the other two being either hyperpolarizing or depolarizing responses from mGluRs. In a cloning study, Chaudhari et al. (Nature Neurosci. 3: 113–119, 2000) reveal a full-length, N-terminus truncated form of an mGluR4 ("taste-mGluR4") that when expressed in heterologous cells responds with decreases in cAMP to millimolar levels of glutamate.
|
FOOTNOTES |
|---|
2 Supported in part by grants from National
Institutes of Health grant DC-00356 and the Department of Veterans
Affairs.
3 Abbreviations used: AMPA,
-amino-3-hydroxy-5-methyl-isoxazole-4-propionate; L-AP4,
L-2-amino-4-phosphonobutyrate; CNS, central nervous system;
GMP, guanosine-5'-monophosphate; IMP, inosine-5'-monophosphate; MSG,
monosodium glutamate; NMDA,
N-methyl-D-aspartate.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONInteraction of glutamate with...Transduction models for umami...SUMMARYREFERENCES |
|---|
1.
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
2. Brand J. G. Biophysics of taste. Beauchamp G. K. Bartoshuk L. eds. Tasting and Smelling. Handbook of Perception and Cognition, 2nd ed. 1997:1-24 Academic Press San Diego, CA.
3. Brand J. G., Teeter J. H., Kumazawa T., Huque T., Bayley D. L. Transduction mechanisms for the taste of amino acids. Physiol. Behav. 1991;49:899-904[Medline]
4. Cagan R. H. Allosteric regulation of glutamate taste receptor function. Kawamura Y. Kare M. R. eds. Umami: A Basic Taste 1987:155-172 Marcel Dekker New York, NY.
5.
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
6. Conn P. J. Patel J. eds. The Metabotropic Glutamate Receptors 1994 Humana Press Totowa, NJ.
7.
Delay R. J., Kinnamon S. C., Roper S. D. Serotonin modulates voltage-dependent calcium current in Necturus taste cells. J. Neurophysiol. 1997;77:2515-2524
8. Faurion A. Are umami taste receptor sites structurally related to glutamate CNS receptor sites?. Physiol. Behav 1991;49:905-912[Medline]
9. Hayashi Y., Mori T., Zviman M. M., Brand J. G., Restrepo D., Teeter J. H. Responses of mouse taste cells to monosodium glutamate and analogues recorded by optical imaging. Chem. Senses 1997;22:699(abs.)
10.
Hayashi Y., Zviman M. M., Brand J. G., Teeter J. H., Restrepo D. Measurement of membrane potential and [Ca2+]i in cell ensembles: applications to the study of glutamate taste in mouse. Biophys. J. 1996;71:1057-1070
11. Hellekant G., Ninomiya Y., Danilova V. Taste in chimpanzees II: single chorda tympani fibers. Physiol. Behav. 1997;61:829-841[Medline]
12. Hollmann M., Heinemann S. Cloned glutamate receptors. Annu. Rev. Neurosci. 1994;17:31-108[Medline]
13. Kawamura Y. Kare M. R. eds. Umami: A Basic Taste 1987 Marcel Dekker New York, NY.
14. Kawamura, Y., Kurihara, K., Nicolaidis, S., Oomura, Y. & Wayner, M. J., eds.(1991) Umami: Proceedings of the Second International Symposium on Umami. Physiol. Behav. (special issue) 49, pp. 831–1030.
15.
Kumazawa T., Kurihara K. Large synergism between monosodium glutamate and 5'-nucleotides in canine taste nerve responses. Am. J. Physiol. 1990;259:R420-R426
16. Kumazawa T., Nakamura M., Kurihara K. Canine taste nerve responses to umami substances. Physiol. Behav. 1991;49:875-881[Medline]
17. Monaghan D. T. Wenthold R. J. eds. The Ionotropic Glutamate Receptors 1997 Humana Press Totowa, NJ.
18. Ninomiya Y., Funakoshi M. Behavioral discrimination between glutamate and the four basic taste substances in mice. Comp. Biochem. Physiol. 1989a;92A:365-370
19. Ninomiya Y., Funakoshi M. Peripheral neural basis for behavioral discrimination between glutamate and the four basic taste substances in mice. Comp. Biochem. Physiol. 1989b;92A:371-376
20. Pin J. P., Bockaert J. Get receptive to metabotropic glutamate receptors. Curr. Opin. Neurobiol. 1995;5:342-349[Medline]
21. Rifkin B., Bartoshuk L. M. Taste synergism between monosodium glutamate and disodium 5'-guanylate. Physiol. Behav. 1980;24:1169-1172[Medline]
22. Rolls E. T. Taste and olfactory processing in the brain and its relation to the control of eating. Crit. Rev. Neurobiol. 1997;11:263-287[Medline]
23. Teeter J. H., Kumazawa T., Brand J. G., Kalinoski D. L., Honda E., Smutzer G. Amino acid receptor channels in taste cells. Corey D. P. Roper S. D. eds. Sensory Transduction 1992:291-306 Rockefeller University Press New York, NY.
24. Torii K., Cagan R. H. Biochemical studies of taste sensation IX. Enhancement of L-[3H]glutamate binding to bovine taste papillae by 5`-ribonucleotides. Biochim. Biophys. Acta 1980;627:313-323[Medline]
25. Yamaguchi S. The synergistic taste effect of monosodium glutamate and disodium 5'-inosinate. J. Food Sci. 1967;32:473-478
26. Yamaguchi, S., ed.(1998) Umami. A Special Issue. Food Rev. Int. 14: 123–337.
27.
Yamaguchi S., Yoshikawa T., Ikeda S., Ninomiya T. Measurement of the relative taste intensity of some L--amino acids and 5'-nucleotides. J. Food Sci. 1971;36:846-849
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
