GABA (gamma-aminobutyric acid) is a non-proteinogenic amino acid initially identified in microorganisms, yet it serves a crucial function in neurotransmission among higher animals. The origins of GABA date back to 1883, when it was first chemically synthesized. It was not until 1950 that researchers detected its presence in mammalian brains, and by 1967, its role as an inhibitory neurotransmitter had been firmly established. Beyond its significance in the animal nervous system, GABA is also essential for plant growth, development, and responses to stress. This review aims to present a detailed examination of GABA's biosynthetic processes, metabolic pathways, physiological roles, applications, and its prospective uses in both medicine and agriculture.
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Biosynthesis and metabolism
Synthesis pathway
Glutamate decarboxylation pathway
The primary pathway for GABA synthesis involves the conversion of glutamate into GABA, a reaction catalyzed by glutamate decarboxylase (GAD) with pyridoxal phosphate (vitamin B6) serving as a necessary coenzyme. In mammalian neurons, GAD plays a crucial role in GABA production, with its enzymatic activity directly influencing synthesis rates. A comparable mechanism operates in plants, where glutamate decarboxylase facilitates the transformation of glutamate into GABA within plant cells, contributing to the regulation of carbon and nitrogen metabolism.
Figure 1. GABA metabolism pathways.
Polyamine degradation pathway
In plants, GABA can also be synthesized through the polyamine degradation pathway. Polyamines are a class of organic compounds containing multiple amino groups, which play an important role in plant growth and development and stress response. During the polyamine degradation process, pyrroline decarboxylase catalyzes glutamate to produce GABA. This pathway is particularly important when plants cope with environmental stresses such as drought and salinity.
Non-enzymatic pathway of proline
Apart from the two primary pathways previously discussed, plants exhibit an alternative, albeit less prevalent, route for synthesis: the non-enzymatic proline conversion pathway. This process involves the transformation of proline into GABA without the involvement of enzymes. Although the precise mechanisms underlying this pathway remain partially unclear, it is recognized to contribute to particular physiological functions within plants.
Metabolic pathways
GABA bypass
The metabolism of GABA in the body is mainly carried out through the GABA bypass. In this pathway, GABA is first converted into succinic semialdehyde under the catalysis of GABA transaminase (GABA-T), and then generates succinic acid under the action of succinic semialdehyde dehydrogenase, and finally enters the tricarboxylic acid cycle (TCA). This process not only completes the metabolism of GABA, but also constitutes another branch of α-ketoglutarate oxidation to succinic acid together with the glutamate decarboxylation reaction catalyzed by glutamate decarboxylase, thus playing an important role in energy metabolism and neurotransmitter balance.
Microbial synthesis
In addition to plant and animal cells, intestinal microorganisms also play an important role in the synthesis of GABA. Beneficial bacteria such as Lactobacillus and Bifidobacterium can use glutamate as a substrate to produce GABA through the enzymatic reaction of GAD. The GABA produced by these microorganisms can regulate the intestinal environment and thus affect the health of the host.
Neurotransmission and receptors
GABAA receptor
GABAA receptor is an ionotropic receptor that is primarily responsible for rapid inhibitory neurotransmission. When GABA binds to the GABAA receptor, the receptor channel opens, allowing chloride ions to flow into the cell, resulting in hyperpolarization and inhibition of the neuron. This rapid action of the GABAA receptor enables it to play a key role in regulating neuronal activity and maintaining the stability of the nervous system. For example, during an epileptic seizure, GABA can quickly inhibit the overexcitation of neurons by activating the GABAA receptor, thereby alleviating epileptic symptoms.
GABAB receptor
Unlike the GABAA receptor, the GABAB receptor is a G protein-coupled receptor that is relatively slow acting. Activation of the GABAB receptor regulates neurotransmitter release and synaptic plasticity through G protein-mediated signaling pathways. Although this receptor has a slower activity, it is able to fine-tune GABA signaling and thus play a role in a wider range of physiological processes. For example, in learning and memory processes, the regulatory role of the GABAB receptor is crucial for the formation and adjustment of neural circuits.
Functional significance
The effects of GABA in the nervous system are mainly achieved through two receptors, GABAA and GABAB. The synergistic action of these two receptors maintains the balance of excitatory and inhibitory neurotransmission, which is essential for the normal development and function of the nervous system. In humans, defects in GABA signaling are associated with a variety of neurocognitive disorders, such as schizophrenia and anxiety. Studies have shown that single nucleotide polymorphisms in the gene encoding the GABAA receptor are sufficient to increase the prevalence of these diseases. Therefore, in-depth research on the function and mechanism of GABA and its receptors is of great significance for the development of new therapeutic strategies.
Physiological functions
Effects in Animals
Nervous system function
As the main inhibitory neurotransmitter, GABA plays a key role in regulating neuronal activity and maintaining the stability of the nervous system. For example, in the treatment of anxiety and insomnia, by enhancing GABA signaling, the patient's symptoms can be effectively relieved. In addition, GABA also plays an important role in the treatment of epilepsy by inhibiting the overexcitation of neurons and reducing the frequency and intensity of epileptic seizures.
Gastrointestinal regulation
GABA also has important physiological functions in the gastrointestinal tract. Studies have shown that GABA can regulate intestinal activity and relieve intestinal inflammation. For example, in the treatment of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), GABA drugs may provide a more comprehensive therapeutic effect by regulating intestinal neuroimmune responses. In addition, the effects of GABA in the intestine may also affect the central nervous system through the gut-brain axis, thereby affecting emotions and behaviors.
Immune system regulation
In recent years, studies have found that GABA also plays an important role in the immune system. For example, GABA can affect the immune response by regulating the inflammatory response of T cells. In autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE), the regulatory effect of GABA may alleviate the progression of the disease by affecting the differentiation and function of T cells. Therefore, the role of GABA and its receptors in immune regulation provides new ideas for the development of new therapeutic strategies.
Role in plants
Growth and development
GABA has multiple physiological functions in plant growth and development. It participates in the carbon and nitrogen metabolism of plants and regulates the growth rate and morphology of plants. For example, in some plants, the accumulation of GABA is closely related to the growth of leaves and the efficiency of photosynthesis. In addition, GABA may also affect the flowering time and fruit ripening of plants by regulating the level of plant hormones.
Stress response
GABA plays a key role in plant responses to environmental stress. Studies have shown that under environmental stresses such as drought, salinity, and low temperature, the level of GABA in plants increases significantly. This increase helps plants reduce the damage caused by stress by regulating osmotic pressure and removing reactive oxygen free radicals. For example, under saline-alkali stress, exogenous application of GABA can increase the activity of antioxidant enzymes in plants, protect the photosynthetic system, and thus enhance the salt tolerance of plants.
Figure 2. A proposed model demonstrates how GABA protects plants from drought stress. (Hasan, MM, et al., 2021)
Applications and therapeutic potential
Medical Application
GABA and its receptors have broad application prospects in the medical field. In the treatment of neurological diseases, GABA drugs are widely used to treat epilepsy, anxiety, insomnia and other diseases. For example, benzodiazepines exert sedative, anti-anxiety and anti-epileptic effects by enhancing the activity of GABAA receptors. In addition, the role of GABA in immune regulation also provides new ideas for the treatment of autoimmune diseases. For example, by regulating the GABA signaling pathway, it may help alleviate the symptoms of diseases such as experimental autoimmune encephalomyelitis.
Agricultural applications
In the agricultural field, the application of GABA is also gaining more and more attention. Studies have shown that exogenous application of GABA can enhance plant tolerance to environmental stress and improve crop yield and quality. For example, under saline-alkali stress, the application of GABA can increase the activity of antioxidant enzymes in plants, protect the photosynthetic system, and thus enhance the salt tolerance of plants. In addition, GABA can also affect plant growth and development and fruit quality by regulating the level of plant hormones. For example, in winter strawberries grown in facilities, exogenous GABA can shorten the vegetative growth time, advance flowering and fruit ripening, and at the same time improve the hardness and antioxidant properties of the fruit.
Industrial production
The industrial production of GABA is mainly carried out through two methods: chemical synthesis and microbial fermentation. Although the chemical synthesis method has a fast reaction speed and high yield, it has problems such as severe reaction conditions, high toxicity of raw materials, and high cost. Therefore, it has gradually been replaced by microbial fermentation. Microbial fermentation has the advantages of mild reaction conditions, high safety factor, and low cost, and has gradually become the mainstream method for producing pharmaceutical and food safety grade GABA.
Research and future directions
Current research
At present, the research on GABA mainly focuses on the following aspects:
Neurodevelopment and disease
1. Neurodevelopment and diseases
GABA plays a key role in neural development, and its function may change with the developmental stage. For example, in the fetal period, GABA mainly behaves as an excitatory neurotransmitter, while in adulthood it mainly behaves as an inhibitory neurotransmitter. GABA receptors (such as GABAA and GABAB) regulate neuronal excitability and inhibition in the interaction between neurons, affecting the stability and function of neural networks. GABA dysfunction is associated with a variety of diseases, including anxiety, depression, schizophrenia, epilepsy, autism spectrum disorder, etc. In addition, abnormalities in GABA in neural development may lead to neurodevelopmental disorders, such as impaired synaptic plasticity and dysfunctional neural networks.
Figure 3. An intracellular process in which GABA or glutamate from neurons are uptake by astrocytes. (Vargas RA, 2018)
Immune and gastrointestinal systems
GABA not only plays a role in the nervous system, but also plays an important role in the immune system and gastrointestinal tract. Studies have shown that GABA can inhibit T cell responses and inflammatory activities by activating GABA receptors, thereby regulating the function of the immune system. In the gastrointestinal tract, GABA participates in regulating gastric juice secretion and intestinal motility through synthesis, storage and release. In addition, GABA has been found to affect the composition of intestinal microbiota, further affecting the immune response.
Plant physiology and stress responses
In plants, GABA is an important signaling molecule involved in regulating plant responses to environmental stresses. Studies have shown that GABA can enhance plant stress resistance by regulating physiological, biochemical, and molecular pathways. For example, under drought and salt stress, GABA protects plants by improving leaf tension, upregulating antioxidant expression, and regulating metabolic pathways. In addition, GABA is also involved in the regulation of plant hormone signals, such as interactions with the abscisic acid (ABA) signaling pathway. These studies provide new perspectives for plant physiology and agriculture.
Future Prospects
In the future, the research and application of GABA will have broader development prospects:
Development of treatment strategies
Develop new therapeutic strategies based on the GABA signaling pathway for the treatment of neurological diseases, autoimmune diseases, and metabolic diseases. For example, small molecule drugs or gene therapy can be used to regulate the activity of GABA receptors to achieve therapeutic effects.
Innovation in agricultural technology
By utilizing the physiological functions of GABA, new agricultural technologies can be developed to improve the stress resistance and yield of crops. For example, through gene editing technology, crop varieties with high GABA content can be cultivated to enhance their tolerance to environmental stress.
Optimization of industrial production
Optimize the industrial production method of GABA to improve production efficiency and product quality. For example, by improving microbial fermentation technology, reduce production costs and increase the yield and purity of GABA.
Conclusion
As an important non-protein amino acid, GABA plays a variety of key roles in the physiological processes of animals and plants. From the inhibitory transmission of the nervous system to the stress response of plants, the functional diversity and importance of GABA are self-evident. With the continuous deepening of research, the application potential of GABA in the fields of medicine, agriculture and industry will be further explored and utilized. In the future, with the continuous emergence of new technologies and new methods, the research and application of GABA will make greater contributions to human health and agricultural development.
References
- Hasan, MM, Alabdallah, NM, Alharbi, BM, et al. (2021). GABA: A Key Player in Drought Stress Resistance in Plants. International Journal of Molecular Sciences, 22(18), 10136. https://doi.org/10.3390/ijms221810136
- Vargas RA (2018) The GABAergic System: An Overview of Physiology, Physiopathology and Therapeutics. Int J Clin Pharmacol Pharmacother 3: 142. doi: https://doi.org/10.15344/2456-3501/2018/142
