Physiology, GABA


Article Author:
Benjamin Jewett


Article Editor:
Sandeep Sharma


Editors In Chief:
Jasleen Jhajj
Cliff Caudill
Evan Kaufman


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
3/14/2019 5:35:55 PM

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]

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]

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]

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]

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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Physiology, GABA - Questions

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Which ionic channel contains the GABA receptor?



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What is the major inhibitory neurotransmitter in the brain?



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A 7-year-old male with cerebral palsy is brought to the neurologist by his mother for a follow-up visit. He has recently been prescribed baclofen, a GABA-B receptor agonist, for spasticity. The patient's mother asks several questions about baclofen and the GABA signaling system. She inquires how the body produces GABA. Which of the following amino acids is the precursor for GABA?



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Which of the following is the correct statement about the role of GABA in the circuits of the basal ganglia?



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Which is true regarding gamma-aminobutyric acid (GABA)?



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A 52-year-old man undergoes a lower anterior resection of the colon and rectum as a treatment for adenocarcinoma of the colon. He experiences postoperative ileus following the operation. On postoperative day 3, he develops confusion and agitation. Heart rate is 135/minute and blood pressure is 160/95 mmHg. He is diaphoretic. A diagnosis of alcohol withdrawal is made. What is the pharmacologic basis for the first-line treatment of this condition?



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An 18-year-old man is brought to the emergency department after he became unresponsive, fell to the ground, and began to have jerking movements of his arms and legs. He continues to have jerking movements in the emergency department. He is accompanied by his friend, who states that the patient has a long history of epilepsy. The emergency department physician administers diazepam to the patient, and the seizure resolves. The physician explains to his student that diazepam works on the GABA-A receptor. Which of the following cellular changes occurs when the GABA-A receptor is stimulated?



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A 72-year-old man presents to his primary care doctor with concerns over "shaking hands." He states that when he reaches for something or tries to carry a glass of water, his hands begin to shake. He is unable to draw a straight line because of this tremor. He notes that his father and grandfather both suffered from this problem as well. The tremor is worse with stress and improved with alcohol. On exam, the patient demonstrates a rhythmic action tremor. He has a full range of facial expressions. There is no gait abnormality or cogwheel rigidity. A medication that amplifies signaling of which of the following neurotransmitters can be used to treat this condition?



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A 50-year-old male is being sedated by an anesthesiologist for an esophagogastroduodenoscopy to evaluate the patient's dysphagia and weight loss. The anesthesiologist administers different medications, including midazolam, a benzodiazepine. Midazolam exerts its effect by increasing signaling of the major inhibitory neurotransmitter in the brain. What is this neurotransmitter?



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In the synthesis of GABA, what molecule is the precursor to GABA and what enzyme and cofactor are needed for synthesis?



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Physiology, GABA - References

References

The Top 5 Neurotransmitters from a Clinical Neurologist's Perspective., Kondziella D,, Neurochemical research, 2017 Jun     [PubMed]
GABA<sub>A</sub> receptor: Positive and negative allosteric modulators., Olsen RW,, Neuropharmacology, 2018 Jan 31     [PubMed]
GABA is the principal fast-acting excitatory transmitter in the neonatal brain., Leinekugel X,Khalilov I,McLean H,Caillard O,Gaiarsa JL,Ben-Ari Y,Khazipov R,, Advances in neurology, 1999     [PubMed]
Limitations of Current GABA Agonists in Neonatal Seizures: Toward GABA Modulation Via the Targeting of Neuronal Cl(-) Transport., Khanna A,Walcott BP,Kahle KT,, Frontiers in neurology, 2013     [PubMed]
GABAergic system in the endocrine pancreas: a new target for diabetes treatment., Wan Y,Wang Q,Prud'homme GJ,, Diabetes, metabolic syndrome and obesity : targets and therapy, 2015     [PubMed]
Striatal synaptic dysfunction and altered calcium regulation in Huntington disease., Raymond LA,, Biochemical and biophysical research communications, 2017 Feb 19     [PubMed]
Medullary ventral surface GABA receptors affect respiratory and cardiovascular function., Yamada KA,Norman WP,Hamosh P,Gillis RA,, Brain research, 1982 Sep 23     [PubMed]
Seizures caused by pyridoxine (vitamin B6) deficiency in adults: A case report and literature review., Tong Y,, Intractable & rare diseases research, 2014 May     [PubMed]
GABA Receptors: Pharmacological Potential and Pitfalls., Jembrek MJ,Vlainic J,, Current pharmaceutical design, 2015     [PubMed]
GABA(A) receptor subtypes as targets for neuropsychiatric drug development., Korpi ER,Sinkkonen ST,, Pharmacology & therapeutics, 2006 Jan     [PubMed]
Medical treatment of dystonia., Termsarasab P,Thammongkolchai T,Frucht SJ,, Journal of clinical movement disorders, 2016     [PubMed]
Hepatic encephalopathy and role of antibenzodiazepines., Hammond JB,Ahmad F,, American journal of therapeutics, 1998 Jan     [PubMed]
Synaptobrevin is essential for secretion but not for the development of synaptic processes., Ahnert-Hilger G,Kutay U,Chahoud I,Rapoport T,Wiedenmann B,, European journal of cell biology, 1996 May     [PubMed]
Neurotransmitter release: the last millisecond in the life of a synaptic vesicle., Südhof TC,, Neuron, 2013 Oct 30     [PubMed]
Pedrón VT,Varani AP,Bettler B,Balerio GN, GABA{sub}B{/sub} receptors modulate morphine antinociception: Pharmacological and genetic approaches. Pharmacology, biochemistry, and behavior. 2019 Mar 6;     [PubMed]
Wang Q,Ren L,Wan Y,Prud'homme GJ, GABAergic regulation of pancreatic islet cells: Physiology and antidiabetic effects. Journal of cellular physiology. 2019 Jan 28;     [PubMed]
Allen MJ,Sharma S, GABA Receptor 2018 Jan;     [PubMed]

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