GRIA3

Protein:

Glutamate Ionotropic Receptor AMPA Type Subunit 3

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Glutamate receptor 3 (GRIA3) is a receptor protein encoded for by the gene GRIA3. Glutamate is an excitatory neurotransmitter which binds to GRIA3 inducing wakefulness. This is in contrast to the action of GABA, which binds to GABA receptors creating a sedative effect which promotes sleep, but also helps maintain the deep sleep which is required to wake feeling rested. As such, the glutamate:GABA ratio is key in modulating sleep and is controlled by the enzyme GAD1 1,2.

There are two SNPs within GRIA3 which have been associated with poor sleep outcomes, although a mechanism for either has not been described. The ‘C’ allele of rs687577 and the ‘A’ allele of rs3848874 have both been associated with depression and fatigue, with a stronger association observed in women.

A17114C

Science Grade
B+
Sleep
rsID Number Major Allele Minor Allele Minor Allele Frequency (%)
rs687577 a c 23

Risk Description

The risk ‘C’ allele of rs687577 in the GRIA3 gene has been associated with depression and reduced sleep duration, with an especially strong association seen in women. No mechanism is described but we can hypothesize that in those with the ‘C’ allele GRIA3 activity is increased, either due to an increase in the numbers of receptors present, or an increase in the excitatory effect which is induced by GRIA3 upon glutamate binding 3.

Indirect Nutrients:*

IngredientActive IngredientEffect
Vitamin B6 Pyridoxal phosphate

GRIA3 is the receptor stimulated by the excitatory neurotransmitter glutamate, which induces a feeling of wakefulness and energy when it binds. In contrast GABA molecules induce a sedative effect, promoting sleep and maintaining deep sleep, improving the feeling of wakefulness and alertness the following morning. Therefore, the glutamate:GABA ratio is critical in modulating sleep, and this ratio is controlled by the enzyme GAD1 which converts glutamate into GABA.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 GRIA3 rs687577, by ensuring that vitamin B6 is not limiting and that GAD1 can function efficiently, in converting glutamate into GABA 4.

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. This may help counteract the increased excitatory effect observed in those with the ‘C’ allele in GRIA3 rs687577 5.

Chamomile Apigenin

Chamomile has a long history of use, as an aid to improve sleep and act as a general relaxant starting with the Romans, Greeks and Egyptians. The key ingredient of chamomile which promotes sleep is the flavone apigenin. Found in many plants, with chamomile flowers being a particularly rich source, the complex molecule apigenin interacts with GABA receptors to induce a sedative effect, promoting sleep and maintaining deep sleep, improving the feeling of wakefulness and alertness the following morning. This may help counteract the increased excitatory effect observed in those with the ‘C’ allele in GRIA3 rs687577 6.

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 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. This may help counteract the increased excitatory effect observed in those with the ‘C’ allele in GRIA3 rs687577 7.

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. This may help counteract the increased excitatory effect observed in those with the ‘C’ allele in GRIA3 rs687577 8.

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

Hops are the flowers of the hop plant. With a bitter flavor, rich in resins, and essential oils, hops are mainly used to flavor and stabilize beer. However, the essential oils derived 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. This may help counteract the increased excitatory effect observed in those with the ‘C’ allele in GRIA3 rs687577 9.

Melatonin

Melatonin is a hormone produced by the body in order to regulate sleep patterns. Produced when the body detects a dark environment (receptors in the eyes are especially important for this) it interacts with melatonin receptors throughout the body to slow cell activity and promote the onset of sleep. Although this effect may only be observed with a history of trouble sleeping. This may help counteract the increased excitatory effect observed in those with the ‘C’ allele in GRIA3 rs687577 10.

Nutritional Contraindications:*

IngredientActive IngredientEffect
Caffeine

A major reason we use caffeine is because of its wakefulness promoting effects. Caffeine induces these effects through the adenosine receptor ADORA2A. When adenosine binds to ADORA2A pathways promoting sleep are initiated. However, whilst caffeine can also bind to ADORA2A it does not induce these pathways. So, by sitting, blocking ADORA2A it prevents the sleep inducing effects of adenosine. Removal of caffeine from your diet is often a recommended step for those with trouble sleeping 11.

L-Glutamic Acid Glutamate

Glutamate is an important excitatory neurotransmitter, it’s activity promotes wakefulness and a feeling of energy when it binds to its receptor GRIA3. The ‘C’ allele of SNP rs687577 has been associated with early morning awakening and an overall poor quality of sleep, although no mechanism has been described. We can hypothesise that the receptor is potentially more sensitive to glutamate inducing a stronger signalling response when it binds, which manifests as an increased feeling of energy. However, this over-activation may lead to issues with falling and staying asleep 12,13.

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

G11395A

Sleep
rsID Number Major Allele Minor Allele Minor Allele Frequency (%)
rs3848874 g a 20

Risk Description

The risk ‘A’ allele of r rs3848874 in the GRIA3 gene has been associated with depression and reduced sleep duration, with an especially strong association seen in women. No mechanism is described but we can hypothesize that in those with the ‘C’ allele GRIA3 activity is increased, either due to an increase in the numbers of receptors present, or an increase in the excitatory effect which is induced by GRIA3 upon glutamate binding 14.

Indirect Nutrients:*

IngredientActive IngredientEffect
Vitamin B6 Pyridoxal phosphate

GRIA3 is the receptor stimulated by the excitatory neurotransmitter glutamate, which induces a feeling of wakefulness and energy when it binds. In contrast GABA molecules induce a sedative effect, promoting sleep and maintaining deep sleep, improving the feeling of wakefulness and alertness the following morning. Therefore, the glutamate:GABA ratio is critical in modulating sleep, and this ratio is controlled by the enzyme GAD1 which converts glutamate into GABA.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 GRIA3 rs3848874, by ensuring that vitamin B6 is not limiting and that GAD1 can function efficiently, in converting glutamate into GABA 4.

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. This may help counteract the increased excitatory effect observed in those with the ‘A’ allele in GRIA3 rs3848874 5.

Chamomile Apigenin

Chamomile has a long history of use, as an aid to improve sleep and act as a general relaxant starting with the Romans, Greeks and Egyptians. The key ingredient of chamomile which promotes sleep is the flavone apigenin. Found in many plants, with chamomile flowers being a particularly rich source, the complex molecule apigenin interacts with GABA receptors to induce a sedative effect, promoting sleep and maintaining deep sleep, improving the feeling of wakefulness and alertness the following morning. This may help counteract the increased excitatory effect observed in those with the ‘A’ allele in GRIA3 rs3848874 6.

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 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. This may help counteract the increased excitatory effect observed in those with the ‘A’ allele in GRIA3 rs3848874 7.

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. This may help counteract the increased excitatory effect observed in those with the ‘A’ allele in GRIA3 rs3848874 8.

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

Hops are the flowers of the hop plant. With a bitter flavor, rich in resins, and essential oils, hops are mainly used to flavor and stabilize beer. However, the essential oils derived 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. This may help counteract the increased excitatory effect observed in those with the ‘A’ allele in GRIA3 rs3848874 9.

Melatonin

Melatonin is a hormone produced by the body in order to regulate sleep patterns. Produced when the body detects a dark environment (receptors in the eyes are especially important for this) it interacts with melatonin receptors throughout the body to slow cell activity and promote the onset of sleep. Although this effect may only be observed with a history of trouble sleeping. This may help counteract the increased excitatory effect observed in those with the ‘A’ allele in GRIA3 rs3848874 10.

Nutritional Contraindications:*

IngredientActive IngredientEffect
Caffeine

A major reason we use caffeine is because of its wakefulness promoting effects. Caffeine induces these effects through the adenosine receptor ADORA2A. When adenosine binds to ADORA2A pathways promoting sleep are initiated. However, whilst caffeine can also bind to ADORA2A it does not induce these pathways. So, by sitting, blocking ADORA2A it prevents the sleep inducing effects of adenosine. Removal of caffeine from your diet is often a recommended step for those with trouble sleeping 11.

L-Glutamic Acid Glutamate

Glutamate is an important excitatory neurotransmitter, it’s activity promotes wakefulness and a feeling of energy when it binds to its receptor GRIA3. The ‘A’ allele of SNP rs3848874 has been associated with early morning awakening and an overall poor quality of sleep, although no mechanism has been described. We can hypothesise that the receptor is potentially more sensitive to glutamate inducing a stronger signalling response when it binds, which manifests as an increased feeling of energy. However, this over-activation may lead to issues with falling and staying asleep 12,13.

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

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