GABA

Gamma aminobutyric acid, commonly known as GABA, is a neurotransmitter with multiple functions in central as well as peripheral nervous system. It is the main inhibitory neurotransmitter present in brain.

It is responsible for decreasing neuronal excitability and taking part in a number of inhibitory nervous signals. GABA deficiency can result in different movement-related diseases.

In this article, we will discuss different aspects of GABA, its structure and synthesis, mechanism of action, functions, diseases, and drugs that can modify its activity in the brain.

Structure and Synthesis and Release

GABA is a naturally occurring amino acid that acts as a neurotransmitter in brain and spinal cord. Like other amino acids, it has a carboxylic (-COOH) group and an amino group (-NH3). It is a derivative of glutamate, a non-essential amino acid that is abundantly present in the body. 

It is synthesized from glutamic acid (glutamate) in the inhibitory neurons. These inhibitory neurons which produce GABA are referred to as GABAergic neurons. The glutamic acid undergoes decarboxylation reaction to form GABA. This reaction is catalyzed by glutamate decarboxylase enzyme.

The release of GABA occurs by the same mechanism as followed by other neurotransmitters. When a nerve impulse reaches the pre-synaptic neuron, it causes degranulation of the vesicles containing GABA.

As a result, GABA is released into the synaptic cleft and is ready to exert its action on both pre-synaptic as well as post-synaptic neurons.

Mechanism of Action

Once released into the synaptic cleft, GABA performs its action by binding to its receptors and initiating chemical responses. These responses result in decreased neuronal excitability of the neurons. There are two types of GABA receptors present in the neurons.

GABAA Receptors

It is an ion channel coupled receptor activated by binding to GABA. Upon activation, it causes an increased Cl influx into the neurons.

GABAB Receptors

These are G-protein coupled receptors that are activated by GABA. Upon activation, they cause increased upregulation and opening of Potassium channels, mediated by secondary messengers. They also inhibit the activity of adenyl cyclase enzyme and are responsible for reduced activity of calcium channels.

Activation of either GABAA or GABAB receptors causes increased depolarization of the neurons. As a result, their threshold potential is increased.

These neurons with increased depolarization have decreased excitability. They don’t respond to the normal neuronal signals. In this way, nerve impulse transmission is inhibited in the pathways involving GABAergic neurons.

Effects of GABA

As an inhibitory neurotransmitter, GABA has a number of effects on CNS as well as the peripheral nervous system.  It participates in a number of daily life activities. Below is given a little detail of different effects GABA has on our body.

Stress relaxation

GABA plays an important role in relieving anxiety and stress. The most important factor that contributes to stress and anxiety disorders is increased neuronal activity in the brain. GABA inhibits the neuronal activity in the cerebral neurons.

In this way, it allows a person to relieve stress and stay away from anxiety. It plays a protective role in anxiety disorders.

Blood Pressure Control

Although GABA mainly acts on the CNS, it also has effects on the peripheral nervous system. Studies have shown that GABA can decrease blood pressure. It can do this by decreasing the sympathetic firing.

Heart Rate

By decreasing the sympathetic firing, GABA can also decrease the heart rate.

Sleep

Sleep is the time when your brain rests. GABA knows how to do this. We have already stated that GABA can decrease the neuronal activity of cerebrum. In this way, it helps a person sleep earlier. GABA mimetic drugs are used to treat insomnia due to this ability of GABA.

Role in Brain Development

GABA is considered to have a considerable role in brain development. Although an inhibitory neuron, it has an excitatory role in brain development.

GABA regulates:

  • Proliferation of neuronal cells
  • Migration and differentiation of newly formed cells
  • Elongation of neurites
  • Formation of synapses

GABA is also responsible for causing cell cycle rest. Once the neurons have developed, it causes them to undergo senescence in S-phase of the cell cycle.

Pain

GABA also plays a role in pain perception. It has an analgesic effect. Being an inhibitory neurotransmitter, GABA can decrease the firing of neurons that carry pain sensations from periphery to brain. It can also slow down the nerve impulses in pain pathway of brain

This is the reason why GABA mimetic drugs and its analogs are used to decrease severe pain as in diabetic neuropathy, post-surgical pain, etc.

Glucagon secretion

GABA also has effects outside the nervous system. GABA is secreted by beta cells of pancreas. It acts on the neighboring alpha calls of the pancreas.

GABA inhibits the alpha cells and prevents glucagon release that would counter the effects produced by insulin.

Immune system

GABA receptors are also present on immune cells. Binding of GABA to these receptors has been shown to decrease the inflammatory response. It promotes the immune regulatory responses that tend to inhibit the autoimmune diseases.

GABA also regulates the release of inflammatory cytokines.

Diseases associated with GABA

Studies have found that altered GABA signaling is associated different brain diseases. The defect in GABA signaling can cause a number of psychiatric diseases.  We will focus on some of these diseases in which GABA signaling is targeted for therapeutic purposes.

Attention Deficit Hyperactivity Disorder (ADHD)

It is a disease characterized by hyperactivity, inattention, and impulsivity. It affects a person in his early age. Patients with ADHD lose control of their behavior. The disease has been linked to defect in GABA signaling, mainly GABA receptors.

Studies have shown that decreased GABA activity is an important factor in the pathogenesis of ADHD.

Epilepsy

Epilepsy is another disorder associated with a defect in GABA receptors. Epilepsy has various types. Epilepsy that occurs in children or teens is associated with ionic changes in postsynaptic GABAA receptors. There is a decreased expression of GABAA receptors. GABA mimetic drugs are therefore used in the treatment regimen of epilepsy.

Depression

Depression is the most important psychiatric disorder in today’s world. GABA plays an important role in controlling the development of hippocampus neurons’ maturation and migration.

The hippocampus is involved in determining the behavior of a person. MRI images have shown decreased hippocampal volume in patients with major depressive disorders. So, GABA is considered to have some significance in depression pathogenesis.

Moreover, some experiments have found that the drugs that inhibit GABA­B receptors have an anti-depressant role.

Anxiety

It is considered that the GABAergic neurons play an important role in mode and behavior. Although decreased GABAergic neurons activity is associated with depressive disorders, decreased GABA activity is also associated with anxiety.

The evidence of this is the fact that drugs that potentiate GABAA receptor are used in anxiety disorders.

Drugs modifying GABA activity

Drugs that bind to GABA receptors are used to treat a number of psychiatric disorders. A brief detail of these drugs is given below.

Benzodiazepines

These drugs bind to the GABAA receptor and increase the frequency of Cl channels. As a result, they potentiate the effects of GABA.

These drugs are used in sleep disturbances, anxiety disorders and for sedation. They are also used as anesthetics. The drugs include diazepam, lorazepam, oxazepam, etc.

Barbiturates

They also bind to GABAA receptors but on a different site than benzodiazepines. They increase the duration of Cl channel opening. They are also used as anesthetics. These include phenobarbital, secobarbital, etc.

Pregabalin

It is a GABA agonist having structural similarity with GABA. It is used to treat conditions like neuropathic pain, post-surgical pain, pain in diabetic neuropathy etc.

Conclusion/Summary

GABA is an inhibitory neurotransmitter in CNS as well as peripheral nervous system.

It is derived from a naturally occurring amino acid, glutamic acid, by decarboxylation reaction. The inhibitory neurons release GABA into the synapse when the nerve impulse reaches the presynaptic terminal.

GABA produces its effects by binding to GABA receptors, that are of two types:

  • GABAA receptors: they are coupled to Cl ion channels and cause Cl influx.
  • GABAB receptors: they are G-protein coupled receptors that activate K+ channels and K+ efflux.

Activation of these receptors results in decreased neuronal excitability which has a number of effects. The systemic effects of GABA include:

  • Stress relaxation and mood elevation
  • Decrease in heart rate
  • Decrease in blood pressure
  • Induction of sleep
  • Decreased inflammatory response
  • Decreased glucagon release
  • Role in brain development
  • Development of synapses

Defect in GABAergic neuronal pathways are associated with a number of disorders, such as:

  • Attention Deficit Hyperkinetic Disorder (ADHD)
  • Epilepsy
  • Depression
  • Anxiety

GABA activity in the CNS and peripheral system can be modified by GABAergic drugs. These drugs include:

  • Benzodiazepines
  • Barbiturates
  • Pregabalin

These drugs are used in conditions like insomnia, anxiety disorders, neuropathic pain, etc. They are also used as anesthetics.

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