GABA and L-Glutamine Balancing Act: methylate Your BRAIN, It Will Work Better; Visit to the Morgue, April 4th 2014, on Mission Hill Street,


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:

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 and the brain. [6]Although the liver is capable of relevant glutamine synthesis, its role 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 acid-base balance, activated immune cells,[7] and many cancer cells.[5] In respect to the last point mentioned, different glutamine analogues, such as DONAzaserine 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 postoperative patients. Glutamine is also marketed as a supplement used for muscle growth in weightliftingbodybuildingendurance, 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 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 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 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 substrate-fortified ACSF and that the mode of action of beta-hydroxybutyrate, pyruvate and lactate (assessed by measurement NAD(P)H and oxygen utilization) was energy metabolism-related.[14]

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]

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 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 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 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 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 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

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 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 blood-brain 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–brain barrier as a prodrug that later hydrolyzes into GABA and niacin.[49]

 

ImagePasadena

In plants

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/S0074-7696(02)13011-7ISBN 978-0-12-364617-0PMID 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 acids regarded as essential for humans are phenylalaninevalinethreoninetryptophanmethionineleucineisoleucinelysine, andhistidine.[1] Additionally, cysteine (or sulphur-containing amino acids), tyrosine (or aromatic amino acids), andarginine 

 

About Drolgalazin

Dr Olga Lazin is a UCLA graduate in History. American Constitutional and Globalization.She is a published author, and History Lecturer at UCLA. You can access and download her books at: http://www.olgalazin.com In Hard copy: Globalization is Decentralized: Easter Europe and Latin America Compared, Civic And Civil Society, Foundations And U.S. Philanthropy, published 2016 Author HOUSE, USA. She has been teaching History at UCLA, Cal State University Dominguez Hills, Cal State University Long Beach, as well as University of Guadalajara (UDG) and University of Quintana Roo, in Mexico for over 26 years. Her specialty is History of Food, Globalization of technology, food History, and the American Constitution. As a hobby, she is practicing permaculture. Her radio show is accessible 24 hours a day at: http://www.blogtalkradio.com/dr_olga_lazin FACEBOOK: OLGA LAZIN DROlga Lazin Twitter; @olgamlazin Instagram; #lazinolga E-mail; olazin@ucla.edu
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3 Responses to GABA and L-Glutamine Balancing Act: methylate Your BRAIN, It Will Work Better; Visit to the Morgue, April 4th 2014, on Mission Hill Street,

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