GABA is sold as a
dietary supplement in many countries. It has been traditionally thought that exogenous GABA (i.e., taken as a supplement) does not cross the
blood–brain barrier, but data obtained from more recent research in rats describes the notion as being unclear.[2][3]
Neurons that produce GABA as their output are called
GABAergic neurons, and have chiefly inhibitory action at receptors in the adult vertebrate.
Medium spiny cells are a typical example of inhibitory
central nervous system GABAergic cells. In contrast, GABA exhibits both excitatory and inhibitory actions in
insects, mediating
muscle activation at synapses between
nerves and muscle cells, and also the stimulation of certain
glands.[6] In mammals, some GABAergic neurons, such as
chandelier cells, are also able to excite their glutamatergic counterparts.[7] In addition to fast-acting phasic inhibition, small amounts of extracellular GABA can induce slow timescale tonic inhibition on neurons.[8]
GABAA receptors are ligand-activated chloride channels: when activated by GABA, they allow the flow of
chloride ions across the membrane of the cell.[5] Whether this chloride flow is depolarizing (makes the voltage across the cell's membrane less negative), shunting (has no effect on the cell's membrane potential), or inhibitory/hyperpolarizing (makes the cell's membrane more negative) depends on the direction of the flow of chloride. When net chloride flows out of the cell, GABA is depolarising; when 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 reduces the effect of any coincident synaptic input by reducing the
electrical resistance of the cell's membrane. Shunting inhibition can "override" the excitatory effect of depolarising GABA, resulting in overall inhibition even if the membrane potential becomes less negative. It was thought that a developmental switch in the molecular machinery controlling the concentration of chloride inside the cell changes the functional role of GABA between
neonatal and adult stages. As the brain develops into adulthood, GABA's role changes from excitatory to inhibitory.[9]
Brain development
GABA is an inhibitory transmitter in the mature brain; its actions were thought to be primarily excitatory in the developing brain.[9][10] The gradient of chloride was reported to be reversed in immature neurons, with its reversal potential 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 (that is, a depolarizing current). The differential gradient of chloride in immature neurons was shown to be primarily due to the higher concentration of NKCC1 co-transporters relative to KCC2 co-transporters in immature cells. GABAergic interneurons mature faster in the hippocampus and the GABA machinery appears earlier than glutamatergic transmission. Thus, GABA is considered the major excitatory neurotransmitter in many regions of the brain before the
maturation of
glutamatergic synapses.[11]
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.[12][13] The
ganglionic eminences also contribute greatly to building up the GABAergic cortical cell population.[14]
Besides the nervous system, GABA is also produced at relatively high levels in the
insulin-producing
beta cells (β-cells) of the
pancreas. The β-cells secrete GABA along with insulin and the GABA binds to GABA receptors on the neighboring
isletalpha cells (α-cells) and inhibits them from secreting
glucagon (which would counteract insulin's effects).[25]
GABA can promote the replication and survival of β-cells[26][27][28] and also promote the conversion of α-cells to β-cells, which may lead to new treatments for
diabetes.[29]
Experiments on mice have shown that hypothyroidism induced by fluoride poisoning can be halted by administering GABA. The test also found that the thyroid recovered naturally without further assistance after the fluoride had been expelled by the GABA.[31]
Immune cells express receptors for GABA[32][33] and administration of GABA can suppress
inflammatory immune responses and promote "regulatory" immune responses, such that GABA administration has been shown to inhibit
autoimmune diseases in several animal models.[26][32][34][35]
In 2018, GABA has shown to regulate secretion of a greater number of cytokines. In plasma of
T1D patients, levels of 26
cytokines are increased and of those, 16 are inhibited by GABA in the cell assays.[36]
In 2007, an excitatory GABAergic system was described in the airway
epithelium. The system is activated by exposure to allergens and may participate in the mechanisms of
asthma.[37] GABAergic systems have also been found in the
testis[38] and in the eye lens.[39]
Structure and conformation
GABA is found mostly as a
zwitterion (i.e., with the
carboxyl group deprotonated and the amino group protonated). Its
conformation depends on its environment. In the gas phase, a highly folded conformation is strongly favored due to the electrostatic attraction between the two functional groups. The stabilization is about 50 kcal/mol, according to
quantum chemistry calculations. In the solid state, an 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.[40][41]
History
In 1883, GABA was first synthesized, and it was first known only as a plant and microbe metabolic product.[42]
In 1959, it was shown that at an inhibitory synapse on crayfish muscle fibers GABA acts like stimulation of the inhibitory nerve. Both inhibition by nerve stimulation and by applied GABA are blocked by
picrotoxin.[43]
Historically it was thought that exogenous GABA did not penetrate the
blood–brain barrier,[2] but more current research[3] describes the notion as being unclear pending further research.
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 (with equivalent efficacy to
lamotrigine based on studies of mice).[49][50] Many of the substances below are known to cause
anterograde amnesia and
retrograde amnesia.[51]
In general, GABA does not cross the
blood–brain barrier,[2] 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.[52] At least one study suggests that orally administered GABA increases the amount of
human growth hormone (HGH).[53] 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.[52] Consequently, considering the potential biphasic effects of GABA on growth hormone production, as well as other safety concerns, its usage is not recommended during pregnancy and lactation.[54]
GABA enhances the
catabolism of
serotonin into
N-acetylserotonin (the precursor of
melatonin) in rats.[55] It is thus suspected that GABA is involved in the synthesis of melatonin and thus might exert regulatory effects on sleep and reproductive functions.[56]
Research has indicated that oral supplementation of GABA does not yield any favorable outcomes in terms of stress reduction and enhancement of sleep quality in human subjects.[57]
Chemistry
Although in chemical terms, GABA is an
amino acid (as it has both a primary amine and a carboxylic acid functional group), it is rarely referred to as such in the professional, scientific, or medical community. By convention the term "amino acid", when used without a
qualifier, refers specifically to an
alpha amino acid. GABA is not an alpha amino acid, meaning the amino group is not attached to the alpha carbon. Nor is it incorporated into
proteins as are many alpha-amino acids.[58]
GABAergic drugs
GABAA receptor ligands are shown in the following table[nb 1]
GABA is also found in plants.[78][79] It is the most abundant amino acid in the
apoplast of tomatoes.[80] Evidence also suggests a role in cell signalling in plants.[81][82]
^Barbin G, Pollard H, Gaïarsa JL, Ben-Ari Y (April 1993). "Involvement of GABAA receptors in the outgrowth of cultured hippocampal neurons". Neurosci. Lett. 152 (1–2): 150–154.
doi:
10.1016/0304-3940(93)90505-F.
PMID8390627.
S2CID30672030.
^Obrietan K, Gao XB, Van Den Pol AN (August 2002). "Excitatory actions of GABA increase BDNF expression via a MAPK-CREB-dependent mechanism—a positive feedback circuit in developing neurons". J. Neurophysiol. 88 (2): 1005–15.
doi:
10.1152/jn.2002.88.2.1005.
PMID12163549.
^Yang H, Xing R, Liu S, Yu H, Li P (2016). "γ-Aminobutyric acid ameliorates fluoride-induced hypothyroidism in male Kunming mice". Life Sciences. 146: 1–7.
doi:
10.1016/j.lfs.2015.12.041.
PMID26724496.
^Xiang YY, Wang S, Liu M, Hirota JA, Li J, Ju W, Fan Y, Kelly MM, Ye B, Orser B, O'Byrne PM, Inman MD, Yang X, Lu WY (July 2007). "A GABAergic system in airway epithelium is essential for mucus overproduction in asthma". Nat. Med. 13 (7): 862–7.
doi:
10.1038/nm1604.
PMID17589520.
S2CID2461757.
^Payne AH, Hardy MH (2007). The Leydig cell in health and disease. Humana Press.
ISBN978-1-58829-754-9.
^Majumdar D, Guha S (1988). "Conformation, electrostatic potential and pharmacophoric pattern of GABA (γ-aminobutyric acid) and several GABA inhibitors". Journal of Molecular Structure: THEOCHEM. 180: 125–140.
doi:
10.1016/0166-1280(88)80084-8.
^W. G. Van der Kloot; J. Robbins (1959). "The effects of GABA and picrotoxin on the junctional potential and the contraction of crayfish muscle". Experientia. 15: 36.
^Schousboe A, Waagepetersen HS (2007). "GABA: Homeostatic and pharmacological aspects". Gaba and the Basal Ganglia - from Molecules to Systems. Progress in Brain Research. Vol. 160. pp. 9–19.
doi:
10.1016/S0079-6123(06)60002-2.
ISBN978-0-444-52184-2.
PMID17499106.
^Chapouthier G, Venault P (October 2001). "A pharmacological link between epilepsy and anxiety?". Trends Pharmacol. Sci. 22 (10): 491–3.
doi:
10.1016/S0165-6147(00)01807-1.
PMID11583788.
^Campagna JA, Miller KW, Forman SA (May 2003). "Mechanisms of actions of inhaled anesthetics". N. Engl. J. Med. 348 (21): 2110–24.
doi:
10.1056/NEJMra021261.
PMID12761368.
^
abMüller EE, Locatelli V, Cocchi D (April 1999). "Neuroendocrine control of growth hormone secretion". Physiol. Rev. 79 (2): 511–607.
doi:
10.1152/physrev.1999.79.2.511.
PMID10221989.
Pinna G, Costa E, Guidotti A (June 2006). "Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake". Psychopharmacology. 186 (3): 362–72.
doi:
10.1007/s00213-005-0213-2.
PMID16432684.
S2CID7799814.
Dubrovsky BO (February 2005). "Steroids, neuroactive steroids and neurosteroids in psychopathology". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 29 (2): 169–92.
doi:
10.1016/j.pnpbp.2004.11.001.
PMID15694225.
S2CID36197603.
^Toraskar, Mrunmayee; Pratima R.P. Singh; Shashank Neve (2010).
"STUDY OF GABAERGIC AGONISTS"(PDF). Deccan Journal of Pharmacology. 1 (2): 56–69. Archived from
the original(PDF) on 2013-10-16. Retrieved 2019-04-01.
Boehm SL, Ponomarev I, Jennings AW, Whiting PJ, Rosahl TW, Garrett EM, Blednov YA, Harris RA (2004). "γ-Aminobutyric acid a receptor subunit mutant mice: New perspectives on alcohol actions". Biochemical Pharmacology. 67 (8): 1581–1602.
doi:
10.1016/j.bcp.2004.07.023.
PMID17175815.
Boehm SL, Ponomarev I, Blednov YA, Harris RA (2006). "From Gene to Behavior and Back Again: New Perspectives on GABAA Receptor Subunit Selectivity of Alcohol Actions". In Enna SJ (ed.). GABA. Advances in Pharmacology. Vol. 54. Elsevier. pp. 171–203.
doi:
10.1016/S1054-3589(06)54008-6.
ISBN978-0-12-032957-1.
PMID17175815.
^Dimitrijevic N, Dzitoyeva S, Satta R, Imbesi M, Yildiz S, Manev H (2005). "Drosophila GABAB receptors are involved in behavioral effects of gamma-hydroxybutyric acid (GHB)". Eur. J. Pharmacol. 519 (3): 246–252.
doi:
10.1016/j.ejphar.2005.07.016.
PMID16129424.
^Awad R, Muhammad A, Durst T, Trudeau VL, Arnason JT (August 2009). "Bioassay-guided fractionation of lemon balm (Melissa officinalis L.) using an in vitro measure of GABA transaminase activity". Phytother Res. 23 (8): 1075–81.
doi:
10.1002/ptr.2712.
PMID19165747.
S2CID23127112.
^Celikyurt IK, Mutlu O, Ulak G, Akar FY, Erden F (2011). "Gabapentin, A GABA analogue, enhances cognitive performance in mice". Neuroscience Letters. 492 (2): 124–8.
doi:
10.1016/j.neulet.2011.01.072.
PMID21296127.
S2CID8303292.