The Brain Hypometabolism Hypothesis Part 97: The Dual Role of the NMDA Receptor

In their paper, Lai, Zhang and Wang examine the effects of Glutamate induced excitotoxicity on the Mitochondria. As per the previous posts, the authors have noted that there is a set-point hypothesis which effectively states that NMDA receptor mediated Calcium influx into the cell is associated either with excitotoxicity or else the promotion of neuronal survival. The authors cite studies on Cerebellar Granule cells which show that low levels of NMDA stimulation of NMDA receptors promotes neuronal survival in contrast with high levels of NMDA stimulation which leads to excitotoxicity.

Context

Contextualising this, excitotoxicity is a process that is mediated by Glutamate via NMDA receptors. This in turn is relevant to the Brain Hypometabolism Hypothesis as states in which energy is reduced can lead to activation of NMDA receptors.

Activated_NMDAR

NMDA Receptor by RicHard-59 (CC BY SA 3.0)

What is the NMDA Receptor?

The NMDA Receptor is an ion channel which is activated by Glutamate. The NMDA Receptor is involved in the response of neurons to ischaemia. The NMDA Receptor is also involved in memory formation in a process referred to as Long Term Potentiation.

In the Brain Hypometabolism Hypothesis there is a focus on the relationship between energy metabolism and neuropathology. The NMDA Receptor and associated metabolic pathways offer a tangible connection between energy metabolism and neuropathology.Monosodium_glutamate_crystals

Crystalline Monosodium Glutamate by Ragesoss (CC BY 3.0)

Lai, Zhang and Wang outline the role of Monosodium Glutamate in their paper. Monosodium Glutamate is a food additive. In a paper published in 1957, Lucas and Newhhouse reported the results of their study looking at the effects of Monosodium Glutamate (MSG) when applied to the mouse retina. The researchers found evidence of neurotoxicity. Further findings confirmed that Glutamate (MSG dissociates into Sodium and Glutamate in solution) is excitatory (i.e. increases the chance of a neuron firing).

What is Excitotoxicity?

Excitoxicity is the damage and death of neurons secondary to Glutamate receptor activation. There is an interesting paper by Lai, Zhang and Wang on excitotoxicity and stroke. The authors look at the targets for neuroprotection following a stroke. Excitotoxicity is related to the NMDA Receptor. This in turn is relevant to the Brain Hypometabolism Hypothesis.

In their paper Lai, Zhang and Wang write that although excitotoxicity was initially investigated in relation to the properties of Monosodium Glutamate it plays an important role in brain trauma and a number of neurodegenerative conditions including

  • Huntington’s Disease
  • Alzheimer’s Disease
  • Amyotrophic Lateral Sclerosis

Excitotoxicity and Excitation

Professor John Olney and colleagues conducted research in 1971 into the excitotoxic effects of Glutamate analogues (Olney et al, 1971). They found that analogues which were excitatory were excitotoxic and those which were not excitatory were not excitotoxic. Contextualising this – the effects of Glutamate are mediated via the NMDA Receptor and excitotoxicity is a pathological process which can result from reduced energy metabolism. This in turn is relevant to the Brain Hypometabolism Hypothesis.

Summarising this:

Excitatory properties are required for excitoxicity

Brain Hypometabolism Hypothesis

The Brain Hypometabolism Hypothesis focuses on energy metabolism. More specifically the hypothesis states that

Energy hypometabolism in the brain leads to neuropathology

What is Metabolism?

Human_Metabolism_-_Pathways

Human Metabolism by Frozen Man (CC BY 4.0)

Metabolism can be defined as the chemical processes that occur in living organisms. There are three types of metabolic processes

(a) Generation of energy

(b) Generation of basic chemicals including fatty acids, amino acids and sugars

(c) Elimination of Nitrogen waste products

Key Pathways in Energy Metabolism

There are several key pathways in energy metabolism in humans. Several pathways result in the formation of Acetyl CoA from fatty acids, amino acids and glucose. Acetyl CoA is utilised in the Citric Acid Cycle. The Citric Acid Cycle generates ATP. The Citric Acid Cycle also generates NADH which is used in Oxidative Phosphorylation which utilises Oxygen as an electron acceptor.

What is Glycolysis?

Glycolysis

Glycolysis is one of the key pathways for energy metabolism in the human body. In this metabolic pathway the molecule Glucose is converted into Pyruvate. This pathway generates energy in the form of ATP. This pathway however does not use oxygen although the products generated are metabolised using oxygen. This is relevant to the bigger picture of energy metabolism in the brain.

1024px-Acetyl-CoA-3D-vdW

Acetyl CoA Space Filling Molecule by Benjah-bmm27 (Public Domain)

What is Acetyl Coenzyme A?

Acetyl Coenzyme A is an important molecule for many pathways involved in energy metabolism. Acetyl Coenzyme A is derived from

(a) Glucose via the Glycolysis pathway

(b) Amino acids via Acetoacetyl-CoA, Pyruvate and directly through multiple pathways

(c) Fatty acids via Beta-oxidation

Vitamin B5 is required for the synthesis of Acetyl CoA.

What is the Citric Acid Cycle?

The Citric Acid Cycle (CC BY 3.0) by Narayanese, WikiUserPedia, YassineMrabet, TotoBaggins, Wadester16

The Citric Acid Cycle is one of the main energy metabolism pathways in humans. Acetyl Co-A which is generated from other pathways is utilised in the Citric Acid Cycle. The Citric Acid Cycle has a number of properties

  1. Generation of energy in the form of ATP
  2. Generating NADH which is utilised in oxidative phosphorylation
  3. Citric Acid is regenerated
  4. Carbon Dioxide is produced

The Citric Acid Cycle takes place in the Mitochondria.

What is Oxidative Phosphorylation?

Oxidative phosphorylation is a series of chemical reactions in which electrons are transferred, nutrients are metabolised and ATP is formed. Nutrients are oxidised and the donated electrons are processed in the electron transport chain. ATP formation via ATP Synthase utilises the electron/proton gradient across the mitochondrial membrane according to the Chemiosmotic Theory.

What is the Chemiosmotic Theory?

The Chemiosmotic Theory is central to the understanding of Oxidative Phosphorylation. Proposed by Dr Peter Mitchell in 1961, the theory states that the energy for ATP generation derives from electrical and chemical gradients resulting from the transfer of electrons and protons across the mitochondrial membrane in the electron transport chain.

1280px-Adenosine-diphosphate-3D-balls

Ball and Stick Model of ADP by Jynto (Public Domain)

What is ADP?

Adenosine Diphosphate (ADP) is a precursor of ATP. ATP is synthesised from ADP and inorganic Phosphate by the enzyme ATP Synthase. ADP contains Adenine and Ribose both of which are also found in RNA.

What is ATP Synthase?

Atp_exp.qutemol-ball

ATP Synthase by ALoopingIcon using QuteMol (CC BY 2.5)

ATP Synthase is an enzyme that combines inorganic phosphate and Adenosine Diphosphate to form Adenosine Triphosphate (ATP). This in turn is used as a source of energy.

What is Complex I?

Complex1

Complex I by Tim Vickers (Public Domain)

The first step in Oxidative Phosphorylation in humans is the transfer of electrons from NAD via Complex I. The structure of Complex I is shown above. Complex I is also known as NADH-coenzyme Q Oxidoreductase. NADH donates electrons to Complex I in a reaction requiring Coenzyme Q10. The electrons are further transferred via Flavin Mononucleotide and Iron-Sulfur Complexes before the transfer of proteins into the intermembrane space.

What is NAD+?

NAD+-from-xtal-2003-3D-balls

NAD+ by Ben Miller (Public Domain)

Nicotinamide Adenine Dinucleotide (NAD) has a number of properties

  1. NAD exists in a reduced (NADH) and oxidised (NAD+) form
  2. NAD is a key molecule in oxidative phosphorylation
  3. NAD is formed by two nucleotides

What is Complex II?

Complex_II

Complex II by FVasconcellos and TimVickers (Public Domain)

Complex II is involved in Oxidative Phosphorylation and is also known as Succinate Dehydrogenase. Succinate is oxidised (donating electrons) to form Fumarate. The donated electrons enter the electron transport chain.

Complex_III_reaction

Complex III by FVasconcellos and TimVickers (Public Domain)

What is Complex III?

Complex III is also known as Q-cytochrome C Oxidoreductase. Complex III contains Cytochromes. Ubiquinol (a reduced form of Coenzyme Q10) donates electrons to Cytochrome C. Electrons are transferred between molecules in a circuit which causes four protons to be transferred across the Mitochondrial membrane for every 2 electrons. This forms part of the electron transport chain.

ATP Synthase is an enzyme that combines inorganic phosphate and Adenosine Diphosphate to form Adenosine Triphosphate (ATP). This in turn is used as a source of energy.

800px-Complex_IV

Complex IV by FVasconcellos and TimVickers (Public Domain)

What is Complex IV?

Complex IV is also known as Cytochrome C Oxidase. Complex IV contains Heme groups, Copper, Magnesium and Zinc. Complex IV facilitates the transfer of electrons to Oxygen in a reaction which results in the formation of water.

Citations

D.R. Lucas, J.P. Newhouse. The toxic effect of sodium l-glutamate on the inner layers of the retina. AMA Arch. Ophthalmol., 58 (1957), pp. 193–201

T. Koike, D.P. Martin, E.M. Johnson Jr. Role of Ca2+ channels in the ability of membrane depolarization to prevent neuronal death induced by trophic-factor deprivation: evidence that levels of internal Ca2+ determine nerve growth factor dependence of sympathetic ganglion cells. Proc. Natl. Acad. Sci. U.S.A., 86 (1989), pp. 6421-6425

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Disclaimer: The comments made here represent the opinions of the author and do not represent the profession or any body/organisation. The comments made here are not meant as a source of medical advice and those seeking medical advice are advised to consult with their own doctor. The author is not responsible for the contents of any external sites that are linked to in this blog.

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