NEUR3001 Lecture Notes - Lecture 4: Neural Tube Defect, Allosteric Regulation, Nicotinamide
Neurochemistry: Basic Neurobiology of Brain
Metabolism
1. Brain Intermediary Metabolism
Glycolysis ↔ Gluconeogenesis
• Unidirectional enzymes (key control points)
o Phosphofructokinase (PFK) ↔ Fructose Diphosphatase (FDPase)
o Hexokinase (HK) ↔ Glucose-6-phosphatase (G6Pase)
o Pyruvate Kinase (PK) favours pyruvate formation
• Little glycogen storage for carbohydrates
o Liver: muscle: brain = 100:10:1
• Highly geared low levels of glycolytic & TCA intermediates
o TCA: low [metabolites], high [glu], [asp], [GABA]
• Very aerobic
o High CO2 output & oxidative phosphorylation
o Low lactate formation
o Partial ischemia: ↑ lactate local ↓ pH dmg
1.1. Brain Work
➢ Brain requires a lot of energy
➢ Need to maintain ion gradients across plasma membrane dependent on ion pumps (require ATP)
➢ ATP-dependent enzymes
1.2. Brain Metabolism & NT Release
➢ Intact TCA cycle required
o ATP synthesis
o NT synthesis
▪ Acetyl in acetylcholine derived from acetyl-CoA
▪ Glutamate & GABA AA transmitters derived from α-ketoglutarate
➢ Hypoxia may result in ↓ NT conc
o Less flux through TCA cycle w/o O2
2. Brain Cell types
2.1. Neurons (& Synapses)
- Neurotransmission is electro-chemical
- Depolarisation propagation of AP down axon
- Neurotransmitters
o Amino Acids
▪ Excitatory: Glutamate & aspartate
▪ Inhibitory: GABA & Glycine
o Biogenic amines
▪ Acetylcholine, NA, dopamine,
serotonin, histamine
o Neuropeptides & hormones
- Receptors & transporters
o E.g. Dopamine
2.2. Glia
- Smaller than neurons
- Support role function
o Maintain ionic balance in glia & neurons
o Site of BBB
o Scavenge (neuron death gliosis)
- Not excitable
- Tumours
3. Blood Brain Barrier
➢ Selectively permeable barrier
➢ Entry of nutrients depends on BBB properties & transport systems
o Endothelial cells of capillaries from tight junctions made of continuous lipid bilayer
o Solutes enter because of lipid solubility
3.1. Amino Acids & Proteins
• Neurons & glia use AA in protein synthesis
• Some AA serve as NT & have key roles in metabolism i.e glutamate
• AA are lipophobic but hydrophilic (not lipid soluble)
• Transporters carry AA across BBB based on size & charge
o Not unique to brain surface only
3.2. Regions w/o BBB
• Receive blood supply from capillaries w/o tight junctions
o Neurons & glia exposed to circulating blood
• Nerve terminals in median eminence release neurohormones into blood
o Hypothalamus release hormones to anterior pituitary (ACTHcortisol)
4. Regulation of Glucose in Brain
➢ Glucose circulation & brain uptake maximises glucose supply for energy production
➢ Blood glucose level regulated within narrow range except during starvation & diabetes
o Body runs out of glucose after fasting 1 day (storage not high) but transports at high amounts
➢ Brain monitors blood glucose & alters behaviour to ensure supply
4.1. Glucose- Energy Substrate
• Primary energy source for brain
• Cross BBB via glucose transporter to enter neuron & glia
• Brain dependence of glucose (utilises ~100g/day, storage ~16-g)
Document Summary
Glycolysis gluconeogenesis: unidirectional enzymes (key control points, phosphofructokinase (pfk) fru(cid:272)tose diphosphatase (cid:894)fdpase, hexokinase (hk) glucose-6-phosphatase (g6pase, pyruvate kinase (pk) favours pyruvate formation. Need to maintain ion gradients across plasma membrane dependent on ion pumps (require atp) Intact tca cycle required: atp synthesis, nt synthesis, acetyl in acetylcholine derived from acetyl-coa, glutamate & gaba aa transmitters derived from -ketoglutarate. Hypoxia may result in nt conc: less flux through tca cycle w/o o2, brain cell types. Depolarisation propagation of ap down axon. Neurotransmitters: amino acids, excitatory: glutamate & aspartate. Inhibitory: gaba & glycine: biogenic amines, acetylcholine, na, dopamine, serotonin, histamine, neuropeptides & hormones. Support role function: maintain ionic balance in glia & neurons, site of bbb, scavenge (neuron death gliosis) Entry of nutrients depends on bbb properties & transport systems: endothelial cells of capillaries from tight junctions made of continuous lipid bilayer, solutes enter because of lipid solubility. Glucose circulation & brain uptake maximises glucose supply for energy production.
