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GLUTAMINE Makes your brain THINK, ANTI
COMATOSE Structure
Glutamine is the most abundant naturally occurring, non essential
amino acid in the human body, and one of the few amino acids that
can directly cross the blood–brain barrier.
Glutamine zwitterionic forms at neutral pH: L-glutamine (left) and D-glutamine
Functions
Glutamine plays a role in a variety of biochemical functions:

Protein synthesis, as any other of the 20 proteinogenic amino acids

Regulation of acid-base balance in the kidney by producingammonium[3]

Cellular energy, as a source, next to glucose[4]

Nitrogen donation for many anabolic processes, including the synthesis
of purines[2]

Carbon donation, as a source, refilling the citric acid cycle[5]

Nontoxic transporter of ammonia in the blood circulation
Producing and consuming organs[edit]
Producers[edit]
Glutamine is synthesized by the enzyme glutamine
synthetase from glutamate and ammonia. The most
relevant glutamine-producing tissue is the muscle mass, accounting for about 90% of
all glutamine synthesized. Glutamine is also released, in small amounts, by the lung
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and the brain.
Although the liver is capable of relevant glutamine synthesis, its role
[6]
in glutamine metabolism is more regulatory than producing, since the liver takes up
large amounts of glutamine derived from the gut.[2]
Consumers[edit]
The most eager consumers of glutamine are the
cells of intestines,[2] the kidney cells for the acidbase balance, activated immune cells,[7] and
many cancer cells.[5] In respect to the last point
mentioned, different glutamine analogues, such
as DON, Azaserine or Acivicin, are tested as
anticancer drugs.
Examples for the usage of glutamine
In catabolic states of injury and illness, glutamine
becomes conditionally essential (requiring intake
from food or supplements).[8] Glutamine has been
studied extensively over the past 10–15 years, and
has been shown to be useful in treatment of
injuries, trauma, burns, and treatment-related side
effects of cancer, as well as in wound healing for
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postoperative patients. Glutamine is also marketed
as a supplement used for muscle growth in
weightlifting, bodybuilding, endurance, and other
sports. Evidence indicates glutamine, when orally
loaded, may increase plasma HGH levels by
stimulating the anterior pituitary gland.[9] In
biological research, L-glutamine is commonly added
to the media in cell culture.[10][11] However, the high
level of glutamine in the culture media may inhibit
other amino acid transport activities.[12]
Glutamine balance gaba.
GABA is excitatory or depolarizing; when the net
chloride flows into the cell, GABA is inhibitory or
hyperpolarizing. When the net flow of chloride is
close to zero, the action of GABA is
shunting. Shunting inhibition has no direct effect on
the membrane potential of the cell; however, it
minimizes the effect of any coincident synaptic input
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essentially by reducing the electrical resistance of
the cell's membrane (in essence, equivalent
to Ohm's law). A developmental switch in the
molecular machinery controlling concentration of
chloride inside the cell – and, hence, the direction of
this ion flow – is responsible for the changes in the
functional role of GABA between the neonataland
adult stages. That is to say, GABA's role changes
from excitatory to inhibitory as the brain develops
into adulthood.[5]
Brain development
While GABA is an inhibitory transmitter in the
mature brain, its actions are primarily excitatory in
the developing brain.[5][6] The gradient of chloride is
reversed in immature neurons, and its reversal
potential is higher than the resting membrane
potential of the cell; activation of a GABA-A receptor
thus leads to efflux of Cl− ions from the cell, i.e. a
4
depolarizing current. The differential gradient of
chloride in immature neurons is primarily due to the
higher concentration of NKCC1 co-transporters
relative to KCC2 co-transporters in immature cells.
GABA itself is partially responsible for orchestrating
the maturation of ion pumps.[7] GABA-ergic
interneurons mature faster in the hippocampus and
the GABA signalling machinery appears earlier than
glutamatergic transmission. Thus, GABA is the major
excitatory neurotransmitter in many regions of the
brain before
the maturation of glutamatergicsynapses.
However, this theory has been questioned based on
results showing that in brain slices of immature mice
incubated in artificial cerebrospinal fluid (ACSF)
(modified in a way that takes into account the
normal composition of the neuronal milieu in
sucklings by adding an energy substrate alternative
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to glucose, beta-hydroxybutyrate) GABA action shifts
from excitatory to inhibitory mode.[8]
This effect has been later repeated when other
energy substrates, pyruvate and lactate,
supplemented glucose in the slices' media.[9] Later
investigations of pyruvate[10] and
lactate[11] metabolism found that the original results
were not due to energy source issues but to
changes in pH resulting from the substrates acting
as "weak acids". These arguments were later
rebutted by further findings[12][13] showing that
changes in pH even greater than that caused by
energy substrates do not affect the GABA-shift
described in the presence of energy substratefortified ACSF and that the mode of action of betahydroxybutyrate, pyruvate and lactate (assessed by
measurement NAD(P)H and oxygen utilization) was
energy metabolism-related.[14]
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In the developmental stages preceding the
formation of synaptic contacts, GABA is synthesized
by neurons and acts both as an autocrine (acting on
the same cell) and paracrine (acting on nearby cells)
signalling mediator.[15][16]The ganglionic
eminences also contribute greatly to building up the
GABAergic cortical cell population.[17]
GABA regulates the proliferation of
neural progenitor cells[18][19] the
migration[20] and differentiation[7][21] the elongation
of neurites[22] and the formation of synapses.[23]
GABA also regulates the growth
of embryonic and neural stem cells. GABA can
influence the development of neural progenitor cells
via brain-derived neurotrophic factor (BDNF)
expression.[24] GABA activates the GABAAreceptor,
causing cell cycle arrest in the S-phase, limiting
growth.[25]
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Beyond the nervous system
mRNA expression of the embryonic variant of the
GABA-producing enzyme GAD67 in a coronal brain
section of a one-day-old Wistar rat, with the highest
expression insubventricular zone (svz). From Popp et
al., 2009.[26]
GABAergic mechanisms have been demonstrated in
various peripheral tissues and organs including, but
not restricted to the intestine, stomach, pancreas,
Fallopian tube, uterus, ovary, testis, kidney, urinary
bladder, lung, and liver.[27]
In 2007, an excitatory GABAergic system was
described in the airwayepithelium. The system
activates following exposure to allergens and may
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participate in the mechanisms
of asthma.[28] GABAergic systems have also been
found in the testis[29] and in the eye lens.[30]
Structure and conformation
GABA is found mostly as a zwitterion, that is, with
the carboxy group deprotonated and the amino
group protonated. Its conformation depends on its
environment. In the gas phase, a highly folded
conformation is strongly favored because of the
electrostatic attraction between the two functional
groups. The stabilization is about 50 kcal/mol,
according to quantum chemistry calculations. In the
solid state, a more extended conformation is found,
with a trans conformation at the amino end and a
gauche conformation at the carboxyl end. This is
due to the packing interactions with the
neighboring molecules. In solution, five different
conformations, some folded and some extended, are
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found as a result of solvation effects. The
conformational flexibility of GABA is important for
its biological function, as it has been found to bind
to different receptors with different conformations.
Many GABA analogues with pharmaceutical
applications have more rigid structures in order to
control the binding better.[31][32]
History
Gamma-aminobutyric acid was first synthesized in
1883, and was first known only as a plant and
microbe metabolic product. In 1950, however, GABA
was discovered to be an integral part of the
mammalian central nervous system.[33]
Bio-synthesis
GABA does not penetrate the blood–brain barrier; it
is synthesized in the brain. It is synthesized
from glutamate using the enzyme L-glutamic acid
decarboxylase and pyridoxal phosphate (which is the
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active form of vitamin B6) as a cofactor. GABA is
converted back to glutamate by a metabolic
pathway called the GABA shunt. This process
converts glutamate, the
principal excitatory neurotransmitter, into the
principal inhibitory neurotransmitter (GABA).[34][35]
Catabolism
GABA transaminase enzyme catalyzes the conversion
of 4-aminobutanoic acid and 2-oxoglutarate
into succinic semialdehyde and glutamate. Succinic
semialdehyde is then oxidized into succinic
acid by succinic semialdehyde dehydrogenase and
as such enters the citric acid cycle as a usable
source of energy.[36]
Pharmacology[edit]
Drugs that act as allosteric modulators of GABA
receptors (known as GABA analogues
or GABAergic drugs) or increase the available
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amount of GABA typically have relaxing, anti-anxiety,
and anti-convulsive effects.[37][38]Many of the
substances below are known to cause anterograde
amnesia and retrograde amnesia.[39]
In general, GABA does not cross the blood–brain
barrier,[40] although certain areas of the brain that
have no effective blood–brain barrier, such as
the periventricular nucleus, can be reached by drugs
such as systemically injected GABA.[41] At least one
study suggests that orally administered GABA
increases the amount of Human Growth
Hormone.[42] GABA directly injected to the brain has
been reported to have both stimulatory and
inhibitory effects on the production of growth
hormone, depending on the physiology of the
individual.[41] Certain pro-drugs of GABA
(ex. picamilon) have been developed to permeate
the blood brain barrier, then separate into GABA
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and the carrier molecule once inside the brain. This
allows for a direct increase of GABA levels
throughout all areas of the brain, in a manner
following the distribution pattern of the pro-drug
prior to metabolism.
GABAergic drugs

GABAA receptor ligands

Agonists/Positive allosteric
modulators: ethanol,[43][44][45] barbiturates, benzod
iazepines, carisoprodol,chloral
hydrate, etaqualone, etomidate, glutethimide, ka
va, methaqualone, muscimol, neuroactive
steroids,zdrugs, propofol, scullcap, valerian, volatile/inhale
d anaesthetics.

Antagonists/Negative allosteric
modulators: bicuculline, cicutoxin, flumazenil, fur
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osemide, gabazine,oenanthotoxin, picrotoxin, Ro
15-4513, thujone.

GABAB receptor ligands

Agonists: baclofen, GBL, propofol, GHB,[46] pheni
but.


Antagonists: phaclofen, saclofen.
GABA reuptake
inhibitors: deramciclane, hyperforin, tiagabine.

GABA-transaminase
inhibitors: gabaculine, phenelzine, valproate, vigab
atrin, lemon balm (Melissa officinalis).[47]

GABA analogues: pregabalin, gabapentin.

Others: GABA (itself), Lglutamine, picamilon, progabide, tetanospasmin.
GABA as a supplement
A number of commercial sources sell formulations
of GABA for use as a dietary supplement, sometimes
for sublingual administration. These sources typically
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claim that the supplement has a calming effect.
These claims are not utterly unreasonable given the
nature of GABA in human sympatholysis, but GABA
as a tranquilizing agent, purely isolated in itself, is
scientifically unsubstantiated or only irregularly
demonstrated. For example, there is evidence stating
that the calming effects of GABA can be observed in
the human brain after administration of GABA as an
oral supplement.[48] However, there is also more
scientifically and medicinally relevant evidence that
pure GABA does not cross the blood–brain barrier at
therapeutically significant levels.[40] The only way to
deliver GABA effectively is to circumvent the bloodbrain barrier. Indeed, there are a small, limited
number of over-the-counter supplements that
are derivatives of GABA, such
as phenibut and picamilon. Picamilon
combines niacin and GABA and crosses the blood–
15
brain barrier as a prodrug that later hydrolyzes into
GABA and niacin.[49]
In plants[edit]
GABA is also found in plants. It is the most
abundant amino acid in the apoplast of
tomatoes.[50] It may also have a role in cell signalling
in plants.[51][52]
See alsSpasticity, Spastic diplegia, a GABA
deficiency neuromuscular neuropathology
References
1. Jump up^ Dawson RMC, Elliot DC, Elliot WH, Jones KM, ed. (1959). Data for Biochemical
Research. Oxford: Clarendon Press.[page needed]
2. Jump up^ Watanabe M, Maemura K, Kanbara K, Tamayama T, Hayasaki H (2002). "GABA
and GABA receptors in the central nervous system and other organs". In Jeon KW. Int.
Rev. Cytol. International Review of Cytology 213. pp. 1–47.doi:10.1016/S00747696(02)13011-7. ISBN 978-0-12-364617-0. PMID 11837891.
IMPORTANT: An essential amino
acid or indispensable amino acid is an amino
acid that cannot be synthesized de novo (from
scratch) by the organism being considered, and
therefore must be supplied in its diet. The amino
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acids regarded as essential for humans
are phenylalanine, valine, threonine, tryptophan, m
ethionine, leucine, isoleucine, lysine,
andhistidine.[1] Additionally, cysteine (or sulphurcontaining amino acids), tyrosine (or aromatic
amino acids), andarginine
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