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Glutamate as a Neurotransmitter - An overview
by Niels Chr. Danbolt
For more references and more information, see: Danbolt,
2001:
Prog. Neurobiol. 65, 1-105.
Glutamate
Outside the community of biomedical scientists, glutamate is probably
best known as "monosodium glutamate" or "MSG" which
is used as a flavor or taste enhancer in food. It is usually available
together with other food additives and spices in most large food stores.
Some people may also have heard the term "Chinese restaurant syndrome"
which is a sudden fall in blood pressure with subsequent fainting after
ingestion of very spicy food. Excessive use of MSG has been suggested
to be the cause, but this is controversial. The use of glutamate as a
food additive, however, is not the reason for the enormous scientific
interest in glutamate.
Glutamate is the major excitatory transmitter in the brain
The main motivation for the ongoing World Wide research on glutamate is
due to the role of glutamate in the signal transduction in the nervous
systems of apparently all complex living organisms, including man. Glutamate
is considered to be the major mediator of excitatory signals in the mammalian
central nervous system and is involved in most aspects of normal brain
function including cognition, memory and learning.
Glutamate is toxic, not in spite of its importance, but because
of it
Glutamate does not only mediate a lot of information, but also information
which regulates brain development and information which determines cellular
survival, differentiation and elimination as well as formation and elimination
of nerve contacts (synapses). From this it follows that glutamate has
to be present in the right concentrations in the right places for the
right time. Both too much and too little glutamate is harmful. This implies
that glutamate is both essential and highly toxic at the same time.
It took a long time to realize that glutamate is a neurotransmitter
It may sound astonishing, but it took the scientific community a long
time to realize that glutamate is a neurotransmitter although it was noted
already 70 years ago that glutamate is abundant in the brain and that
it plays a central role in brain metabolism. Ironically, the reason for
the delay seems to have been its overwhelming importance. Brain tissue
contains as much as 5 - 15 mmol glutamate pr kg, depending on the region,
more than of any other amino acid. Glutamate is one of the ordinary 20
amino acids which are used to make proteins and takes parts in typical
metabolic functions like energy production and ammonia detoxification
in addition to protein synthesis. It was hard to believe that a compound
with so many functions and which is present virtually everywhere in high
concentrations could play an additional role as transmitter.
How glutamate works as a transmitter
Like other signaling substances (neurotransmitters and hormones) the signaling
effect of glutamate is not dependent on the chemical nature of glutamate,
but on how cells are programmed to respond when exposed to glutamate.
Only cells with glutamate receptor proteins (“glutamate receivers”)
on their surfaces are sensitive to glutamate. Glutamate exerts its signaling
function by binding to and thereby activating these receptor proteins.
Several subtypes of glutamate receptors have been identified: NMDA, AMPA/kainate
and metabotropic receptors (mGluR).
Although the individual receptor subtypes show specific (restricted) localizations,
glutamate receptors of one type or another are found virtually everywhere.
Most of the nerve cells, and even glial cells, have glutamate receptors.
Glutamate must be kept inside the cells (intracellularly)
At first glance this looks like an impossible system. A closer look, however,
reveals that glutamate is not present everywhere. It is almost exclusively
located inside the cells. The intracellular location of some 99.99 % of
brain glutamate is the reason why this system can work. This is essential
because glutamate receptors can only be activated by glutamate binding
to them from the outside. Hence, glutamate is relatively inactive as long
as it is intracellular.
The volume of brain cells and of the meshwork formed by their intermingled
extensions, constitute about 80 % of brain tissue volume. This network
is submerged in a fluid, the extracellular fluid which represents the
remaining 20 % of brain tissue volume. The normal (resting) concentration
of glutamate in this fluid is low, in the order of a few micromolar. In
contrast, the glutamate concentration inside the cells is several thousand
times higher, at around 1 - 10 millimolar. The highest glutamate concentrations
are found in nerve terminals and the concentration inside synaptic vesicles
may be as high as 100 millimolar.
The glutamate transporters remove glutamate from the extracellular
fluid
It follows from the description above that the mechanisms which can maintain
low extracellular concentrations of glutamate are essential for brain
function. The only (significant) mechanism for removal of glutamate from
the extracellular fluid is cellular uptake of glutamate; the so called
“glutamate uptake”. This uptake is mediated by a family of
special transporter proteins which act as pumps. These proteins bind glutamate,
one molecule at the time, and transfer them into the cells. In agreement
with the abundance of glutamate and the ubiquity of glutamate receptors,
brain tissue displays a very high glutamate uptake activity. This was
noted already in 1949, although its true importance was not recognized
until after the excitatory action of glutamate was discovered in the 1950s
and 1960s.
Glutamate is taken up into both glial cells and nerve terminals. The former
is believed to be the more important from a quantitative point of view.
Glutamate taken up by astroglial cells is converted to glutamine. Glutamine
is inactive in the sense that it cannot activate glutamate receptors,
and is released from the glial cells into to extracellular fluid. Nerve
terminals take up glutamine and convert glutamine back to glutamate. This
process is referred to as the glutamate-glutamine, and is important because
it allows glutamate to be inactivated by glial cells and transported back
to neurons in an inactive (non-toxic) form.
Types of glutamate transporting proteins
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