Balancing Excitatory Amino Acid Transporter Activity

Regulating EAATs To Balance Glutamate

Controlling Excitatory Amino Acid Transporters (EAATs) activity is a novel way to reduce excitotoxicity (neuronal damage due to overactivity) in the brain. R

 
http://onlinelibrary.wiley.com/doi/10.1111/jnc.13200/full

http://onlinelibrary.wiley.com/doi/10.1111/jnc.13200/full

 

Basics

L-glutamate serves a number of roles in the central nervous system, being an excitatory neurotransmitter, metabolite, and building block in protein synthesis. R

Excitatory Amino Acid Transporters (EAATs) are proteins that play a critical role in glutamatergic neurotransmission by clearing excess glutamate from the synaptic cleft. R R

Properly functioning EAATs activity makes sure there are no excessive amounts of synaptic glutamate.

EAAT In The Brain

Glutamate can be manufactured or taken from the diet through the gut and cross the blood brain barrier. R

 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3580837/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3580837/

 

When in the brain, astrocytes take up extra glutamate (95% of glutamate uptake activity in brain) after synaptic release for a few reasons: R

  1. Ensure a high signal:noise ratio during neurotransmission (highest plasticity in cerebellum & hippocampus) R
  2. Maintain low extracellular glutamate concentration levels
  3. Prevent neurotransmitters from leaking out of synapses going to neighboring synapses

The speed at which EAATs work to balance glutamate and glutamine levels in the body is very important. R

This is because excessive amounts of glutamate can cause excitotoxicity in the brain, as glutamate is the primary activation neurotransmitter. R

Glutamine is rather benign in the cell in this state.

Excessive amounts of glutamate in the brain can continually activate, for example, NMDA receptors, allowing extracellular calcium to enter the cell causing disruption of cell homeostasis, thus causing the cell to die. R

This specific action may be mitigated by NMDA antagonists.

 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC533886/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC533886/

 

If glutamate excitotoxicity is combined with a leaky blood brain barrier, then you can get fatigued easily.

Excitatory Amino Acid Transporters

EAATs are part of the solute carrier 1 (SLC1) family. R

There are 5 EAATs:

  • EAAT1 - astrocytes, mitochondria, and blood (GLAST) R R R
  • EAAT2 - makes up 90% of all EAATs in the brain and represents up to 1% of total brain proteins (GLT1) R R
  • EAAT3 - postsynaptic neuronal carrier (EAAC1) R
  • EAAT4 - neuronal transporter R
  • EAAT5 - exclusive to retinal cells R R

Conditions Associated With Low EAAT Activity

These conditions have lower EAAT activity, so increasing EAAT may help:

  • Addiction (cocaine, heroin, alcohol/binge drinking, and nicotine) R R
  • Alzheimer's Disease R R R
  • ALS R
  • Anhedonia R
  • Anxiety R R
  • Autism R
  • Brain Cancer R R
  • Brain Trauma R
  • Chronic Pain (and Neuropathy) R R R
  • Chronic Stress R
  • Cytomegalovirus R
  • CFS/Fibromyalgia/CIRS/Lyme Disease (my speculation for those who are "wired/tired")
  • Epilepsy R R R
  • Depression R
  • Dementia R
  • Headaches R
  • HIV (with encephalitis) R
  • Huntington's Disease R
  • IBS (possibly) R
  • Manganism R
  • Mercury Poisoning R
  • Multiple Sclerosis R R
  • Neuroinflammation R R
  • Neuromyelitis Optica R
  • Obsessive Compulsive Disorder R
  • Parkinson's Disease R
  • Rett Syndrome R
  • Spinal Cord Injury R
  • Stroke (Ischemic and Hemorrhagic - increases first then decreases) R R

Conditions Associated With High EAAT Activity

These conditions have higher EAAT activity, so decreasing EAAT may help:

  • Hyperammonia R
  • Schizophrenia R

Ways To Increase EAAT Activity

It is important to note that keeping a circadian rhythm may help balance out EAATs as well as reducing chronic inflammation. R

 
 

Supplements:

Hormones And Neurotransmitters:

Drugs And Chemicals:

  • Amitriptyline R
  • Amphetamines R
  • Ceftriaxone (CF is strong, other Beta-Lactam Antibiotics like Ampicillin also increase EAAT2) R R R
  • Dexamethasone (and other glucocorticoids) R R
  • Fasudil Acid R
  • GT949 and GT951 R
  • Guanosine R
  • Ketamine (in NAc) R
  • LDN-212320 R
  • Levodopa R
  • Losartan R
  • Minocycline R
  • MS-153 R
  • Nicergoline R
  • Oxazepam (inhibits EAAT1 in low doses and increases it at higher doses) R
  • Parawixin1 R
  • Pyridazine Derivatives R
  • Riluzole R
  • Stem Cells R
  • Sulbactam R
  • THC (Marijuana) R
  • Trichostatin A R
  • Tobacco (harmine increases, nicotine decreases) R
  • Valproic Acid R

Devices:

  • Electrical Stimulation (possibly) 

Pathways And Peptides:

  • Adenosine R
  • AMPK R
  • Arundic Acid R
  • AT1R Inhibition R
  • ATP R
  • β-catenin R
  • bFGF R
  • BDNF R
  • cAMP R
  • CB1 Agonists R
  • EGF R
  • GDNF R
  • GSK3β R
  • HDAC inhibitors (I and II) R
  • IGF-1 R 
  • JAK2 R
  • mTOR R
  • NRF2 R
  • PDE inhibitors R
  • PDGF R
  • PKC R
  • RARβ (RXR decreases EAAT) R
  • RFX1 R
  • Seladin-1/DHCR24 R
  • SOD R
  • TGF-α R
  • Tumor Necrosis Factor Alpha (increases in microglia) R R 
  • YB-1 R

Ways To Decrease EAAT Activity

 
 

Supplements: 

Drugs:

  • Bromocriptine R
  • Diazepam R
  • Ketamine (in hippocampus) R
  • Nicotine R
  • Tianeptine R

Pathways:

  • AEG R
  • AMPA agonists R
  • AP-1 (c-fos and c-jun) R
  • Caspace 3 R
  • DHPG R
  • Dopamine R
  • Endothelin-1 R
  • Hsp90 R
  • KBBP Inhibition R
  • Nitric Oxide R
  • PTEN R
  • Retinoic Acid (and retinoid × receptor, RXR, agonists) R
  • Tat (HIV) R
  • Tumor Necrosis Factor Alpha (decreases in astrocytes and oligodendroglia) R R 
  • Yin Yang 1 R

Other:

Mechanism Of Action

 
http://physrev.physiology.org/content/93/4/1621

http://physrev.physiology.org/content/93/4/1621

 

Simply, axons put out glutamate and astrocytes break them down into glutamine. R

  • In Axons - Glutamine in extracellular space (via EAAT) -> Glutamate in axon (via Glutaminase) -> stored in VGUT (via VGLUT) -> Glutamate in synapse (via AP) R
  • In Astrocytes - Glutamate in synapse (via EAAT) -> Glutamate in astrocyte -> Glutamine (via Glutamine Synthase) -> dumped back into extracellular space for axon to use (via System "N")
  • EAAT activation stimulates GLUT. R
  • Glutamate can possibly get into the blood via a leaky blood brain barrier. R

Genetics

SLC1A33

    • rs114846327
      • associated with Trypanosoma Cruzi Seropositivity R
    • rs2731880
      • TT had worse executive functions, verbal fluency, and verbal memory vs C carrier group (T lower expression of EAAT1) R
    • Unknown SNP or in placement of gene
      • Heterozygous mutation can lead to decreased glutamate uptake, which can contribute to neuronal hyperexcitability to cause seizures, hemiplegia, and episodic ataxia. R

    SLC1A2

    • rs1042113
      • associated with Schizophrenia and ALS R
    • rs10768122
      • G allele associated with increased risk of Vitiligo R
    • rs3794087
      • associated with Essential Tremor R
    • rs4083482
      • T allele (P=2.00*10-6) associated as risk for Omega-6 Polyunsaturated Fatty Acid Measurement R
    • rs4354668
      • TT had better executive functions and working memory performances vs G carriers (G lower expression of EAAT2) R
    • Unknown SNP or in placement of gene
      • A allele had higher tendency to have migraines R
      • an asparagine for a serine at position 206 in the EAAT2/GLT-1 gene (mutation N206S) was reported in sporadic ALS R
      • Association to risk of alcoholism R
      • Association with higher glutamate concentrations and higher frequency of progressing stroke R
      • Association with higher glutamate concentration in relapsing multiple sclerosis R
      • There was a significant increase of the frequency of the A603 allele in the antisocial alcoholics compared with either the control subjects R

    SLC1A1

    • rs12682807
      • A allele was over-transmitted in patients with OCD (both genders) R
      • Shows significant association with OCD R
    • rs2228622
      • A allele showed a significant association with AAP-induced OC symptoms R
      • A and G alleles associated with early onset obsessive-compulsive disorder R R
      • AA may confer a susceptibility to OC symptoms in schizophrenia patients receiving clozapine R
      • Association at predicting susceptibility to AED resistance R
      • Antiserotonergic SGAs such as clozapine was more prevalent in the subgroup of patients with comorbid OCS R
      • G increased the probability of higher treatment resistance in addiction R
    • rs301430
      • C allele has more anxiety than T carriers in children with ASD R
      • T allele is significantly associated with early-onset OCD R
      • T and C genotype is significantly associated with OCD R
    • rs3087879
      • C allele associated with OCD R
      • polymorphism associated with OCD R
    • rs3780412
      • showed significant association with AAP-induced OC symptoms
      • susceptibility allele for early-onset OCD (in males) R
      • associations with OCD R
    • rs3780413
      • G showed a significant association with AAP-induced OC symptoms R
      • Antiserotonergic SGAs such as clozapine was more prevalent in the subgroup of patients with comorbid OCS R
    • rs7856675
      • AA alleles are associated with increase risk in coronary artery calcification vs GG R 

    SLC1A5

    • rs3027956
      • African (G = 0.957 C = 0.043) associated with breast cancer R
      • Asian (G = 0.524 C = 0.476) associated with breast cancer R
      • Caucasian (C = 0.710 G = 0.290) associated with breast cancer R

    SLC25A12

    • rs2056202
      • C allele was significantly associated with increased risk autism R R
      • T allele was significantly associated with a decreased risk of ASD R

    More Research

    • Supplementing glutamine will not change glutamate levels in the brain. R