GAD1

Protein:

Glutamate Decarboxylase 1


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Glutamate decarboxylase 1 (GAD1) is an enzyme encoded for by the gene GAD1 which is only expressed in the brain. GAD1 converts glutamtate into γ-aminobutyric acid (GABA). GABA molecules are the chief inhibitory neurotransmitter in the body, responsible for dampening down the nervous system. This dampening of neuronal activity is responsible for creating a sedative effect which promotes sleep, but also helps maintain the deep sleep which is required to wake feeling rested. This important role is well known as many hypnotic drugs used in surgery target GABA receptors. Low GABA levels are often associated with insomnia 1.

Whilst GABA molecules are inhibitory neurotransmitters, glutamate is an excitatory neurotransmitter, so the balance of GABA to glutamate is thought to be key in regulating sleep 2.

GAD1 is only expressed in the brain as GABA molecules cannot pass the blood-brain barrier (they cannot leave the brain). However, the amino acid glutamate, which is converted by GAD1 into GABA molecules, can pass the blood-brain barrier. For this reason, supplementation with GABA is not recommended as it will not reach the brain where it is required, and simply be passed out the body 3.

There are two SNPs within GAD1 that are associated with poor outcomes, although a mechanism for either has not been described. The ‘C’ allele of G638+315C and the ‘A’ allele of C170814316A are both associated with depression, early awakenings and fatigue.

G638+315C

Science Grade
B+
Sleep
rsID Number Major Allele Minor Allele Minor Allele Frequency (%)
rs769407 g c 22

Risk Description

The ‘C’ allele of G638+315C is associated with depression, early awakenings and fatigue. Whilst no mechanism has been described we can hypothesize that GAD1 activity is reduced in those with the ‘C’ allele leading to a reduction in the amount of GABA molecules being produced, or an alteration in the GABA, glutamate balance 4.

Direct Nutrients:*

IngredientActive IngredientEffect
Vitamin B6 Pyridoxal phosphate

GAD1 is an enzyme which converts the excitatory neurotransmitter glutamate into the inhibitory neurotransmitter GABA. Glutamate induces a feeling of wakefulness and energy whereas GABA induces a sedative effect, promoting sleep and maintaining deep sleep, improving the feeling of wakefulness and alertness the following morning. As such the glutamate:GABA ratio controlled by GAD1 is critical in controlling sleep. GAD1 uses vitamin B6 as a cofactor, in the absence of vitamin B6 the activity of GAD1 will be reduced. Supplementation may benefit those with the ‘C’ allele in GAD1 G638+315C, ensuring that vitamin B6 is not limiting and that GAD1 can function efficiently 5.

Magnesium

Magnesium has been shown to improve sleep length and quality by interacting with GABA receptors to induce a sedative effect, promoting sleep and maintaining deep sleep, improving the feeling of wakefulness and alertness the following morning. Supplementation may benefit those with the ‘C’ allele in GAD1 G638+315C, if they are lacking in natural GABA molecules, by providing an alternative GABA receptor stimulation 6.

Chamomile Apigenin

Chamomile has been used to improve sleep and as a general relaxant since Roman times. The key sleep promoting ingredient of chamomile is the flavone apigenin. Found in many plants, with chamomile flowers being a particularly rich source, apigenin interacts with GABA receptors to induce a sedative effect, promoting and maintaining deep sleep, improving the feeling of wakefulness and alertness the following morning. Supplementation may benefit those with the ‘C’ allele in GAD1 G638+315C, if they are lacking in natural GABA molecules, by providing an alternative GABA receptor stimulation 7.

Passion Flower Vitexin

Passion flowers are a large group of vine growing plants, originally found in tropical regions but now grown much more extensively. Long been used by Native Americans to make a tea used to treat insomnia; this practice was rapidly adopted by European colonists. The key ingredient of passion flower for promoting sleep has been identified as vitexin, which is derived from apigenin. It is thought to act in a similar fashion to apigenin, promoting good quality, deep sleep and reducing restlessness, by interacting with GABA receptors to induce a sedative effect, promoting sleep and maintaining deep sleep, improving the feeling of wakefulness and alertness the following morning. Supplementation may benefit those with the ‘C’ allele in GAD1 G638+315C, if they are lacking in natural GABA, by providing an alternative GABA receptor stimulation 8.

Indirect Nutrients:*

IngredientActive IngredientEffect
Adenosine

Adenosine is the native molecule which binds to the ADORA2A receptor. It is released upon the breakdown of ATP, the cells “energy currency”. In the brain a large amount of ATP is used when awake, leading to an increasing concentration of adenosine. Upon binding with ADORA2A adenosine induces sleep, especially when present at high doses, so the natural build up of adenosine in the brain during the day is used to promote sleep, allowing the brain to recover its energy stores 9.

Supplementation may benefit those with the ‘C’ allele in GAD1 G638+315C, by promoting sleep through stimulation of adenosine, rather than GABA receptors.

Hops 2-methyl-3-buten-2-ol (MB)

Hops are the flowers of the hop plant. With a bitter flavor and rich in resins, and essential oils, hops are typically used to flavor and stabilize beer. However, the essential oils isolated from hops have also long been used in herbal remedies for the treatment of anxiety and insomnia. The active ingredient of hops, 2-methyl-3-buten-2-ol (MB), mimics the activity of adenosine by binding with ADORA2A and inducing sleep, it has even been shown that MB can out compete caffeine and promote sleep 10.

Supplementation may benefit those with the ‘C’ allele in GAD1 G638+315C, by promoting sleep through alternative stimulation of adenosine, rather than GABA receptors.

Melatonin

The hormone melatonin is produced by the body to regulate sleep patterns. It is produced when the body detects a dark environment (receptors in the eyes are especially important for this) and interacts with melatonin receptors throughout the body to slow cell activity thus promoting sleep 11.

Supplementation may benefit those with the ‘C’ allele in GAD1 G638+315C, by promoting sleep through stimulation of melatonin receptors, rather than GABA receptors.

Nutritional Contraindications:*

IngredientActive IngredientEffect
Caffeine

Caffeine induces wakefulness by blocking the binding of adenosine to its receptor ADORA2A. When adenosine binds to ADORA2A pathways promoting sleep are initiated. However, caffeine binds and blocks this activation promoting wakefulness 12.

In those with the ‘C’ allele in GAD1 G638+315C, where reduced levels of GABA are detected, caffeine should be avoided in the evening as to avoid further impairment of sleep inducing pathways.

L-Glutamic Acid Glutamate

Glutamate is an important excitatory neurotransmitter, it’s activity promotes wakefulness and a feeling of energy. It is converted by the enzyme GAD1 into GABA molecules. GABA molecules bind with their receptors to induce a sedative effect, promoting sleep and maintaining deep sleep, improving the feeling of wakefulness and alertness the following morning.

The balance between glutamate and GABA is thought to be key in regulating sleep. It is hypothesized that in those with the ‘C’ allele in GAD1 G638+315C that GAD1 activity is reduced, leading to a shortage of GABA molecules and an imbalance in the glutamate:GABA ratio, which leads to problems falling asleep and staying asleep. As such additional supplementation with glutamate is to be avoided 1315.

Discuss this information with your doctor before taking any course of action.

C170814316A

Science Grade
B-
Sleep
rsID Number Major Allele Minor Allele Minor Allele Frequency (%)
rs12185692 c a 27

Risk Description

The ‘A’ allele of C170814316A is associated with depression, early awakenings and fatigue. Whilst no mechanism has been described we can hypothesize that GAD1 activity is reduced in those with the ‘A’ allele leading to a reduction in the amount of GABA molecules being produced, or an alteration in the GABA, glutamate balance 16.

Direct Nutrients:*

IngredientActive IngredientEffect
Vitamin B6 Pyridoxal phosphate

GAD1 is an enzyme which converts the excitatory neurotransmitter glutamate into the inhibitory neurotransmitter GABA. Glutamate induces a feeling of wakefulness and energy whereas GABA induces a sedative effect, promoting sleep and maintaining deep sleep, improving the feeling of wakefulness and alertness the following morning. As such the glutamate:GABA ratio controlled by GAD1 is critical in controlling sleep. GAD1 uses vitamin B6 as a cofactor, in the absence of vitamin B6 the activity of GAD1 will be reduced. Supplementation may benefit those with the ‘A’ allele in GAD1 C170814316A, ensuring that vitamin B6 is not limiting and that GAD1 can function efficiently 5.

Magnesium

Magnesium has been shown to improve sleep length and quality by interacting with GABA receptors to induce a sedative effect, promoting sleep and maintaining deep sleep, improving the feeling of wakefulness and alertness the following morning. Supplementation may benefit those with the ‘A’ allele in GAD1 C170814316A, if they are lacking in natural GABA molecules, by providing an alternative GABA receptor stimulation 6.

Chamomile Apigenin

Chamomile has been used to improve sleep and as a general relaxant since Roman times. The key sleep promoting ingredient of chamomile is the flavone apigenin. Found in many plants, with chamomile flowers being a particularly rich source, apigenin interacts with GABA receptors to induce a sedative effect, promoting and maintaining deep sleep, improving the feeling of wakefulness and alertness the following morning. Supplementation may benefit those with the ‘A’ allele in GAD1 C170814316A, if they are lacking in natural GABA molecules, by providing an alternative GABA receptor stimulation 7.

Passion Flower Vitexin

The vine growing passion flowers, originally found in tropical regions but now grown much more extensively, have long been used by Native Americans to make a tea used to treat insomnia. A practice which was rapidly adopted by European colonists.

The key ingredient of passion flower for promoting sleep has been identified as vitexin. It is thought to act in a similar fashion to apigenin, promoting good quality, deep sleep and reducing restlessness, by interacting with GABA receptors to induce a sedative effect, promoting and maintaining deep sleep whilst also improving the feeling of wakefulness and alertness the following morning. Supplementation may benefit those with the ‘A’ allele in GAD1 C170814316A, if they are lacking in natural GABA, by providing an alternative GABA receptor stimulation 8.

Indirect Nutrients:*

IngredientActive IngredientEffect
Adenosine

Adenosine is the molecule which binds to the ADORA2A receptor. It is released when ATP, the cells “energy currency” is broken down. The brain uses a large amount of ATP when awake, leading to an increasing concentration of adenosine. Upon binding with ADORA2A adenosine induces sleep, especially when present at high doses. Therefore the natural build up of adenosine in the brain during the day is used to promote sleep, allowing the brain to recover its energy stores overnight 9.

Adenosine supplementation may benefit those with the ‘A’ allele in GAD1 C170814316A, by promoting sleep through stimulation of adenosine, rather than GABA receptors.

Hops 2-methyl-3-buten-2-ol

Hops are the flowers of the hop plant, with a bitter flavor and rich in resins, and essential oils, hops have traditionally been used to flavor and stabilize beer. The essential oils isolated from hops have also been used in herbal remedies for the treatment of anxiety and insomnia. The active ingredient of hops is 2-methyl-3-buten-2-ol (MB), which mimics the activity of adenosine by binding with ADORA2A and inducing sleep, it has even been shown that MB can out compete caffeine and promote sleep 10.

Supplementation may benefit those with the ‘A’ allele in GAD1 C170814316A, by promoting sleep through alternative stimulation of adenosine, rather than GABA receptors.

Melatonin

The hormone melatonin is produced by the body to regulate sleep patterns. It is produced when the body detects a dark environment (receptors in the eyes are key in detecting this change) and interacts with melatonin receptors in the body to slow cell activity thus promoting sleep 11.

Supplementation with melatonin may benefit those with the ‘A’ allele in GAD1 C170814316A, by promoting sleep through stimulation of melatonin receptors, rather than GABA receptors.

Nutritional Contraindications:*

IngredientActive IngredientEffect
Caffeine

Caffeine induces wakefulness and a feeling of energy by blocking the binding of adenosine to its receptor ADORA2A. Normally when adenosine binds to ADORA2A, pathways promoting sleep are initiated. However, caffeine also binds to ADORA2A and blocks this activation promoting wakefulness 12.

In those with the ‘A’ allele in GAD1 C170814316A, where reduced levels of GABA are detected, caffeine should be avoided in the evening as to avoid further impairment of sleep inducing pathways.

L-Glutamic Acid Glutamate

Glutamate is an excitatory neurotransmitter which wakefulness and a feeling of energy. It is converted by GAD1 into GABA molecules. GABA molecules bind with their receptors to induce a sedative effect, promoting sleep and maintaining deep sleep, improving the feeling of wakefulness and alertness the following morning.

The balance between glutamate and GABA is important in regulating sleep. It is hypothesized that in those with the ‘A’ allele in GAD1 C170814316A that GAD1 activity is reduced, leading to a shortage of GABA molecules and an imbalance in the glutamate:GABA ratio, leading to problems falling and staying asleep. Therefore additional supplementation with glutamate is to be avoided 1315.

Discuss this information with your doctor before taking any course of action.

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