Re: Physiology, GABA - 운동을 하면 흥분성 상태를 정상화할 수 있다.

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. 2019 Sep 1;232:116667.

 doi: 10.1016/j.lfs.2019.116667. Epub 2019 Jul 18.

The effect of exercise on GABA signaling pathway in the model of chemically induced seizures

Mitra Barzroodi Pour 1, Mohamad Bayat 2, Freshteh Golab 3, Mina Eftekharzadeh 4, Majid Katebi 5, Mansoureh Soleimani 6, Fariba Karimzadeh 7

Affiliations expand

• PMID: 31326567
• DOI: 10.1016/j.lfs.2019.116667

Abstract

Aims: Gamma amino butyric acid (GABA) imbalance plays a critical role in most neurological disorders including epilepsy. This study assessed the involvement of mild exercise on GABA imbalance following by seizure induction in rats.

Main methods: Seizure was induced by pentylentetrazole (PTZ) injection. Animals were divided into sham, seizure, exercise (EX), co-seizure-induced exercise (Co-SI EX) and Pre-SI EX groups. In the Co-SI EX group, doing exercise and seizure induction was carried out during four weeks. Animals in the Pre-SI EX group exercised in week 1 to week 8 and seizures were induced in week 5 to week 8. Seizure properties, neural viability and expressions of glutamic acid decarboxylase 65 (GAD65) and GABAA receptor α1 in the hippocampus were assessed.

Key findings: Seizure severity reduced and latency increased in the Co-SI EX and Pre-SI EX groups compared to seizure group. The mean number of dark neurons decreased in all exercise groups compared to seizure group in both CA1 and CA3 areas. The gene level of GAD65 and GABAA receptor α1 was highly expressed in the Co-SI EX group in the hippocampal area. Distribution of GAD65 in the both CA1 and CA3 areas increased in the EX and Co-SI EX groups. GABAA receptor α1 was up-regulated in the CA3 area of Co-SI EX group and down-regulated in the CA1 and CA3 areas of Pre-SI EX group.

Significance: These findings suggest that exercise develop anti-epileptic as well as neuroprotective effects by modulating of GABA disinhibition.

운동은 GABA disinhibition의 조절을 통해 신경을 보호할 뿐만 아니라 간질과 같은 흥분성을 떨어뜨림. 

Physiology, GABA

Benjamin E. Jewett; Sandeep Sharma.

Author Information and Affiliations

Last Update: July 25, 2022.

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Introduction

Gamma-aminobutyric acid (GABA) is an amino acid that serves as the primary inhibitory neurotransmitter in the brain and a major inhibitory neurotransmitter in the spinal cord. It exerts its primary function in the synapse between neurons by binding to post-synaptic GABA receptors which modulate ion channels, hyperpolarizing the cell and inhibiting the transmission of an action potential. The clinical significance of GABA cannot be underestimated. Disorder in GABA signaling is implicated in a multitude of neurologic and psychiatric conditions. Modulation of GABA signaling is the basis of many pharmacologic treatments in neurology, psychiatry, and anesthesia.[1][2][3]

감마아미노뷰티르산(, GABA)은 뇌의 주요 억제 신경전달물질이자 척수의 주요 억제 신경전달물질로 작용하는 아미노산이다. 시냅스 후 GABA 수용체에 결합하여 이온 채널을 조절하고 세포를 과분극화하며 활동전위의 전달을 억제함으로써 뉴런 사이의 시냅스에서 주요 기능을 발휘한다. GABA의 임상적 중요성은 과소평가될 수 없다. GABA 신호의 장애는 많은 신경학적, 정신적 조건과 관련이 있다. GABA 신호의 조절은 신경학, 정신 의학 및 마취에서 많은 약리학적 치료의 기초이다.

Cellular

GABA is synthesized in the cytoplasm of the presynaptic neuron from the precursor glutamate by the enzyme glutamate decarboxylase, an enzyme which uses vitamin B6 (pyridoxine) as a cofactor. After synthesis, it is loaded into synaptic vesicles by the vesicular inhibitory amino acid transporter. SNARE complexes help dock the vesicles into the plasma membrane of the cell. When an action potential reaches the presynaptic cell, voltage-gated calcium channels open and calcium binds to synaptobrevin, which results in the fusion of the vesicle with the plasma membrane and releases GABA into the synaptic cleft where it can bind with GABA receptors. GABA can then be degraded extracellularly or taken back up into glia or the presynaptic cell. It is degraded by GABA-transaminase into succinate semialdehyde which then enters the citric acid cycle. 

GABA binds to two major post-synaptic receptors, the GABA-A and GABA-B receptors. The GABA-A receptor is an ionotropic receptor that increases chloride ion conductance into the cell in the presence of GABA. The extracellular concentration of chloride is normally much higher than the intracellular concentration. Consequently, the influx of negatively charged chloride ions hyperpolarizes the cell, inhibiting the creation of an action potential. The GABA-B receptor functions via a metabotropic G-protein coupled receptor which increases postsynaptic potassium conductance and decreases presynaptic calcium conductance, which consequently hyperpolarizes the postsynaptic cell and prevents the conduction of an action potential in the presynaptic cell. Consequently, regardless of binding to GABA-A or GABA-B receptors, GABA serves an inhibitory function.[4][5][6]

Development

Due to extracellular concentrations of chloride being lower than intracellular levels in the developing brain, GABA has an excitatory role in the fetal and neonatal brain. When GABA-A receptors open chloride channels in the developing brain, the cell becomes hypopolarized and thus more likely to fire an action potential. Consequently, drugs that increase GABA signaling have been reported to be of limited efficacy in the treatment of seizures in preterm neonates.

Organ Systems Involved

GABA is found throughout the human body, though the role that it plays in many regions remains an area of active research. GABA is the primary inhibitory neurotransmitter in the brain, and it is a major inhibitory neurotransmitter in the spinal cord. The insulin-producing beta-cells of the pancreas produce GABA. It functions to inhibit pancreatic alpha cells, stimulate beta-cell growth, and convert alpha-cells to beta cells. GABA also has been found in varying low concentrations within other organ systems, though the significance and function of this are unclear.[7]

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Function

Because GABA is the fundamental neurotransmitter for inhibiting neuronal firing, its function is determined by the neural circuit that it is inhibiting. It is involved in complex circuits throughout the central nervous system. For example, GABA is released by striatal neurons in both the direct and indirect pathways projecting to the globus pallidus, which in turn extends GABA neurons to other brain areas, inhibiting unwanted motor signals. Another example is that GABA signaling in the medulla is involved in the maintenance of respiratory rate. Increased GABA signaling reduces the respiratory rate. A third example is found in the spinal cord, where GABA serves in the inhibitory interneurons. These neurons help to integrate excitatory proprioceptive signals, allowing for the spinal cord to integrate sensory information and create smooth movements.[8][9][10]

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Pathophysiology

GABA is involved in several disease states:

• Pyridoxine deficiency is a rare disease in which the vitamin is not available for the synthesis of GABA. It usually presents as frequent seizures during infancy that are resistant to treatment with anticonvulsants but responds very well to vitamin supplementation.

• The clinical features of hepatic encephalopathy are thought to be due to elevated ammonia levels binding to the GABA-A/GABA complex and increasing chloride ion permeability. 

• The symptoms of Huntington disease are partially caused by a lack of GABA in the striatal projections to the globus pallidus.

• Dystonia and spasticity are believed to be related to a deficiency in GABA signaling.[11][12][13]

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Clinical Significance

GABA is of great clinical significance. Medications that act on the GABA receptor are commonly used as therapeutic medications and substances of abuse, and it is unlikely that any physician, regardless of specialty, will not encounter clinical situations that involve GABA.

There are numerous uses for drugs that modulate GABA signaling. Benzodiazepines are a drug class that exerts its effects by binding to the GABA-A receptor, resulting in increased chloride ion permeability by changing the frequency with which the chloride channels open. They are used in surgical anesthesia, the treatment of epilepsy, REM-sleep disorders, alcohol withdrawal, essential tremor, and muscle spasticity. They are also common drugs of abuse. Ethanol, one of the oldest and most widely-used psychoactive substances, also exerts effects on the GABA-A receptor. Alcohol withdrawal is treated with GABA modulating drugs, such as benzodiazepines. Furthermore, ethanol and benzodiazepines exhibit cross-tolerance with one another due to their similar mechanism of action. Overdosing or taking multiple GABA modulating drugs can result in respiratory depression due to increased GABA signaling in the medulla of the brain stem.

Many other drugs modulate GABA signaling, including the following:

• Barbiturates, sedative drugs which increase the duration at which the chloride channel is open when GABA binds the GABA-A receptor

• Vigabatrin, an antiepileptic inhibitor of GABA transaminase

• Propofol, a sedative commonly used in general anesthesia and allosteric modulator and agonist of the GABA-A receptor

• Flumazenil, a benzodiazepine antagonist which binds to the GABA-A receptor and can reverse benzodiazepine intoxication and improve mental status in hepatic encephalopathy

• Baclofen, a muscle relaxant and GABA-B agonist

• Valproic acid, a mood stabilizer and anti-epileptic that is hypothesized to have an inhibitory effect on GABA uptake

• Zolpidem, a sedative-hypnotic, exerts its effects on the GABA-A receptor

• Gabapentin, commonly prescribed to treat neuropathic pain, partially exerts its effects by increasing GABA synthesis via modulation of glutamate dehydrogenase[14][15][16][17]

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