Second International Conference on Glutamate: Conference
Summary.1
John D. Fernstrom
Departments of Psychiatry, Pharmacology and Neuroscience and UPMC Center for
Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
The Second International Conference on Glutamate focused broadly on the following four
areas: 1) the function of glutamate in taste and as a flavoring agent in foods [as a salt,
usually monosodium glutamate (MSG)]; 2) the participation of glutamate in carbohydrate and
amino acid metabolism; 3) the role of glutamate as a neurotransmitter; and 4) the safety of
glutamate in the food supply (when it is added as MSG).
The taste properties of glutamate included an examination of the glutamate sensors in the
oral cavity that are thought to participate in taste perception. Glutamate occurs naturally in
many foods (e.g., tomatoes, cheeses) and in prepared stocks and soups (in meat and fish
stocks and in soups, the glutamate released by protein hydrolysis becomes a key flavoring
agent); in each case, glutamate adds to the food’s taste. It is also added to prepared foods in
crystalline form to enhance flavor. The flavor attributed to MSG becomes more complex, and
the tongue’s sensitivity to it is enhanced markedly in the presence of certain nucleotides.
This taste is readily identified in Asian cultures as being distinct from the four basic tastes
(sweet, sour, salty, bitter), and has been named "umami" by the Japanese (Yamaguchi and
Ninomiya 2000 ). Western cultures have had difficulty in describing this taste, and thus
heretofore have not identified it as unique (e.g., "savory" and "meaty" are sometimes used to
describe this flavor in Western cultures) (Löliger 2000 , Yamaguchi and Ninomiya 2000 ).
However, as discussed in several reports at the conference, research on "umami" over the
past 25 years, which has included both behavioral and neurophysiologic approaches,
appears to have succeeded in establishing it as a fifth basic taste, alongside sweet, sour,
salty and bitter. The importance attached by the body to the perception of this taste appears
underscored by the identification in the hypothalamus (a brain area important in appetite
control) and the orbital prefrontal cortex (a brain area important in the perception of taste and
smell) of neurons that respond selectively to the application of MSG to the tongue (Nishijo et
al. 2000 , Rolls 2000 ). Currently, it is not known why animals developed an ability to taste
umami or why it might be perceived as pleasant. One speculation has been that it may
provide a signal to the animal that a protein-containing food is being ingested (Kondoh et al.
2000 ).
The past two decades have witnessed an explosion of information on the biochemical and
molecular features of neuronal glutamate receptors (Nakanishi et al. 1998 ,Ozawa et al.
1998 ). Because the umami taste is linked inextricably to glutamate sensing, it is thus not
surprising to find receptor methodologies now being applied to the search for specific
glutamate receptors in the oral cavity. The working hypothesis is that glutamate taste
sensors may be glutamate receptors bearing structural and pharmacologic similarities to
those characterized in brain (in which glutamate is a neurotransmitter) (Brand 2000 ). Using
behavioral and neurophysiologic paradigms (e.g., examining the depolarization rates of taste
fibers after the application of glutamate agonists and antagonists to the tongue), together
with biochemical and molecular tools, investigators have begun to define some of the
molecular characteristics of this taste transduction process. As noted in several reports at the
conference, glutamate taste transduction may involve one or more receptors that are similar,
but probably not identical to brain glutamate receptors (Brand 2000 , Kurihara and
Kashiwayanagi 2000 , Ninomiya et al. 2000 ). If taste physiologists and pharmacologists find
that biochemical and molecular tools developed to examine brain glutamate receptors are
adaptable to their study in the oral cavity, it is likely that great strides will be made over the
next 20 years in defining the molecular basis of the "umami" taste.
In addition to glutamate receptors in the oral cavity, the occurrence of glutamate sensors
(presumably receptors) elsewhere in the digestive system was discussed at the conference.
Most notably, neurophysiologic evidence was presented regarding the ability of glutamate,
applied locally within the small intestine, to stimulate sensory afferents of the vagus nerve.
This stimulation was found to induce a reflex activation of efferent fibers from the brain to the
pancreas and elsewhere, which conceivably might function to facilitate digestion, and
nutrient absorption and distribution (Niijima 2000 ).
Once absorbed from the gut, glutamate quickly becomes an important participant in key
metabolic activities throughout the body. As discussed at the conference, recent evidence
using stable isotopes shows that dietary glutamate is a major energy source for the
intestines, accounting for half of the energy consumed during digestion (Reeds et al. 2000 ).
The role of glutamate as a cosubstrate in the transamination and deamination of several
other amino acids was also reviewed. These reactions provide carbon skeletons for
gluconeogenesis or ATP generation (Brosnan 2000 ). A discussion of nitrogen elimination, a
necessary corollary of gluconeogenesis, focused on the roles of both glutamate and
glutamine in hepatic nitrogen elimination via urea synthesis (Watford 2000 ). Overall, as
succinctly noted by Brosnan, "no other amino acid displays such remarkable metabolic
versatility."
In considering nitrogen movement in the body, both Brosnan (2000) and Watford (2000)
noted that glutamate concentrations are high intracellularly (not extracellularly), consistent
with the idea that glutamate is important in intracellular nitrogen transfer reactions, whereas
the opposite is true for glutamine, i.e., this amino acid appears to have as a focus the
shuttling of nitrogen among cells and organs. This important distinction reappears when
glutamate and glutamine compartmentation in neurons and glia is discussed.
Finally, Battaglia (2000) reviewed recent data regarding glutamate shuttling in the fetus. The
placenta (much like the intestines in adults) utilizes glutamate as an important source of
energy. Indeed, the placenta is said to account for >60% of the total fetal glutamate disposal
rate. The fetal liver has been identified as the key provider of glutamate, although the
placenta is fully capable of utilizing maternal-derived glutamate as well.
Currently, it is not known why the intestines and the placenta consume large quantities of
glutamate for energy generation. As noted at the conference, however, this phenomenon
may explain why glutamate concentrations in plasma and blood rise relatively modestly after
large MSG or glutamate doses have been ingested by adults (either as MSG added to food
or as glutamate contained in food proteins) (Tsai and Huang 2000 ), and why fetal plasma
and blood glutamate concentrations do not rise in response to marked elevations in maternal
plasma and blood glutamate concentrations (Stegink et al. 1975 ).
Generally, the view was expressed that more is known about the metabolism of essential
than nonessential amino acids (such as glutamate). The relative paucity of data on
nonessential amino acids was thought to follow from the technical difficulty in quantitating the
rapid turnover and complex metabolism of these amino acids. Stable isotopic methods now
appear capable of handling such difficulties, as demonstrated by the studies discussed by
Reeds (2000) . They offer a positive indication that a great deal more information will be
forthcoming regarding the details of the metabolism of glutamate and other nonessential
amino acids.
The discussion then shifted to brain, in which endogenous glutamate functions as an
excitatory neurotransmitter (i.e., it causes depolarization of neurons). The depolarizing
property of glutamate has been known for half a century (Fonnum 1984 ). But details on
glutamate’s role as a transmitter have emerged only recently, particularly with the advent of
biochemical and molecular methodologies for identifying and characterizing glutamate
receptors and transporters. Because glutamate excites neurons, it was noted that it has the
potential, when neuronal release is uncontrolled, to overexcite them and cause their death
(Meldrum and Garthwaite 1990 ). This notion led to the concept of glutamate as an
excitotoxin, along with the suggestion that dietary glutamate (e.g., in the form of MSG) might
also be excitotoxic to brain neurons (Meldrum 1993 , Olney 1994 ). However, because
animals ingest large quantities of glutamate daily (both as the free amino acid and as a
constituent of protein) and use glutamate in a variety of metabolic roles in the body, it was
recognized early on that the brain is well protected from the rest of the body with respect to
these large glutamate fluxes (Pardridge 1979 ). This view has only been reinforced by work
conducted over the past two decades (Smith 2000 ). Indeed, even work examining the
neurotoxicity of certain dietary glutamate agonists such as ß-N-methylaminoalanine and
domoic acid (Meldrum 1993 ) failed to support the concept of dietary glutamate toxicity
because these agents gain access to brain via transport mechanisms different from the
glutamate transporter (i.e., they are not effectively excluded from brain, like glutamate,
because they do not use the same transporter) (Smith 2000 ).
Given the large concentrations of glutamate that are present normally in brain, it was further
recognized that potent mechanisms must exist within brain that strictly compartmentalize the
amino acid locally. Indeed, the glutamate present in and used by the brain as a
neurotransmitter has been found to be synthesized within neurons, and actively removed
from the synapse (once released) to be recycled to the neuron in nonneurotransmitter form
(glutamine; it is converted back to glutamate in the neuron). Glial cells are primary
participants in the process of synaptic glutamate removal and recycling (Daikhin and Yudkoff
2000 , Yudkoff et al. 1993 ). These latter functions of glial cells may also help to explain why
neural elements in a portion of the brain lying outside the blood-brain barrier (the median
eminence, a part of the hypothalamus) are not destroyed when blood glutamate
concentrations are made artificially high. Tanycytes, a specialized glial cell present
throughout the median eminence, may effectively maintain low intracellular glutamate
concentrations in this region, even in the face of large glutamate influxes secondary to
greatly elevated blood glutamate concentrations. Only when glutamate influx becomes
unusually high may the glutamate concentrating power of these cells fail (e.g., when
neonatal mice are given extremely high parenteral doses of glutamate), leading to local
glutamate increases and neuronal toxicity (Goldsmith 2000 ).
Overall, the low rate of glutamate penetration into brain, together with the occurrence in brain
of the metabolic machinery for compartmentalizing the actions of glutamate, evidently affords
great protection to brain neurons from accidental or purposeful vagaries in systemic and
local brain glutamate concentrations. Questions remain for the future, however, and one is
particularly relevant to the present discussion, i.e., if glutamate is carefully modulated in its
access to glutamate receptors within the brain, what constraints are there on this interaction
outside the brain (particularly, outside of the blood-brain barrier and away from potent
glutamate uptake transporters on glia)? Glutamate receptors likely occur on the tongue, on
vagal afferent fibers and also on a variety of other cells types in the periphery, where they
may subserve signaling functions (Erdo 1991 , Dingledine and Conn 2000 ). Are these
glutamate receptors protected from the pools of glutamate around them that subserve
metabolic roles, and if so, how? And as a corollary, are the metabolic pools of glutamate the
source of the glutamate molecules that stimulate these receptors, or do neurons exist that
provide the glutamate stimuli (no such neurons have yet been identified)? Perhaps these
questions will be resolved in time for the next symposium.
Finally, because of glutamate’s ubiquity in the food supply, both as a natural constituent and
as an added, flavor-enhancing agent (MSG), the issue of adverse reactions to MSG was
considered at the conference. Over the past 30 years, dietary MSG has been reputed to
induce a variety of unwanted effects in humans, including sweating, muscle pain and fatigue,
headache, skin reactions and asthma. Are these effects real, and if so, are they attributable
to actions of dietary glutamate or MSG? Although the occurrence of one or more adverse
responses to MSG has been reported repeatedly in the published literature, study design has
invariably left questions regarding outcome bias, either on the part of the subject or the
experimenter. As discussed by several clinical investigators at the conference, by today’s
scientific standards, such effects rarely occur in studies in which both experimenter and
experimentee are carefully blinded to the treatment, in which the subjects’ medical conditions
are adequately controlled (a particularly important consideration in the design of asthma
studies) and in which the criteria for identifying MSG responders include their showing both a
reproducible, positive response to MSG and a reproducible nonresponse to the placebo
(Geha et al. 2000 , Simon 2000 , Stevenson 2000 ).
Few molecules of biological importance appear to have as many roles in body function as
glutamate. Among these roles, it functions as a tastant on the tongue (a flavoring agent in
food), a metabolic fuel in the gastrointestinal tract, an amino acid constituent of proteins, a
carbon skeleton that shuttles amino groups among amino acids, a participant in hepatic
ammonia detoxification, an energy substrate for the placenta, a neurotransmitter in brain and
also a signaling molecule for cells outside the brain. This symposium provided an
assessment of our knowledge regarding these (and other) glutamate functions since the
glutamate symposium in 1978. Remarkable advances have been made, and the consensus
at the meeting was that there appears to be every likelihood that the discovery process will
continue unabated over the next 20 years.
FOOTNOTES
1
Presented at the International Symposium on Glutamate, October 12–14, 1998 at the
Clinical Center for Rare Diseases Aldo e Cele Daccó, Mario Negri Institute for
Pharmacological Research, Bergamo, Italy. The symposium was sponsored jointly by the
Baylor College of Medicine, the Center for Nutrition at the University of Pittsburgh School of
Medicine, the Monell Chemical Senses Center, the International Union of Food Science and
Technology, and the Center for Human Nutrition; financial support was provided by the
International Glutamate Technical Committee. The proceedings of the symposium are
published as a supplement to The Journal of Nutrition. Editors for the symposium publication
were John D. Fernstrom, the University of Pittsburgh School of Medicine, and Silvio
Garattini, the Mario Negri Institute for Pharmacological Research.
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