Neurotransmitters Flashcards
What are the three most abundant lipids found in myelin sheath?
Cholesterol, plasmalogen, galactosylcerebroside
Can myelin be synthesized without cholesterol?
No. Cholesterol makes up more than 40% of myelin’s lipids and is the rate-limiting step for myelin formation. (Myelin is 70% lipids : 30% protein)
Plasmalogen functions
Antioxidants, main phospholipid in myelin
Galactosylcerebroside functions
Extremely hydrophobic, acts as extracellular glue in myelin
What are the two main protein components of myelin?
- Proteolipid (PLP) in CNS or Protein zero (P0) in PNS
- Myelin basic protein (MBP)
Proteolipid (PLP) in CNS or Protein zero (P0) in PNS
Extracellular leaflet. Very hydrophobic protein that aids in myelin compaction
Myelin basic protein (MBP)
Helps to stabilize myelin from inside by binding to negative charges on both sides of it
Gangliosides in peripheral nerves
Primarily localized in outer leaflets of plasma membranes and involved in
1. cell-cell recognition
2. Adhesion
3. Signal transduction
Antibodies to ganglioside causes
Guillain-Barré syndrome
What are 4 causes of decreased reflexes?
- ALS: amyotrophic lateral sclerosis
- GBS: guillain barre
- CIDP: chronic inflammatory demyelinating polyneuropathy
- Hypothyroidism
Name 4 main nutrients that are allowed transport across BBB
- GLUT1, GLUT3 transporters allow the brain to use Glucose as fuel.
- Monocarboxylic transporters e.g. lactate, pyruvate, acetate, ketone bodies
- Large neutral amino acids (LAT1) allow LNAAs e.g. Phe, Tyr, Trp, Leu, Ile, Val, Met, His
- Cationic amino acid transporter e.g. Lys, Arg, Ornithine
Why are small neutral amino acids sometimes transported out via the Alanine-preferring-system carrier?
They are used as neurotransmitters in the brain. Letting large amounts of them in will disrupt neural firing.
GLUT1 def syndrome
GLUT1 is used as glucose transporters in endothelial cells lining the BBB. Deficiency causes neonatal seizures within the first month of life, developmental delay, and complex motor disorder due to insufficient energy to the brain. Treatment is ketogenic diet
What is the hierarchy of nutrients the brain will use for energy?
- Glucose
- Ketone bodies during starvation, diabetes, or breastfed neonate
- Lactate during vigorous exercise
EATT
Excitatory amino acid transporters that take up Glutamate into astrocytes to turn them into glutamine before returning them to neurons.
Astrocytes will send … to neurons after using up glucose.
Lactate
Which enzyme’s activity in the glycolytic pathway is higher in neurons?
Pyruvate dehydrogenase: PDH, active TCA and Ox-Phos
How are small molecule neurotransmitters synthesized?
Enzymes are synthesized at the cell body, and the precursors are recycled near the presynaptic terminal from the synaptic cleft.
How are neuropeptides synthesized?
Propeptides and enzymes within vesicles are sent from the cell body. Enzymatic cleavage to transform them into smaller active peptide neurotransmitter is done nearer to the presynaptic terminal.
How is glutamate synthesized?
- Alpha-ketoglutarate (reduction via enz. GDH or transamination via GABA transaminase)
- ย่อยจาก glutamine
Excitotoxicity
Glutamate is unique in that when they act on neuronal
cell bodies they can produce so much calcium influx that neutrons die. Glutamate excitotoxicity occur when cellular energy reserve depleted e.g. failure of energy-dependent reuptake pumps in ischemic stroke. Excess glutamate in synaptic cleft & overstimulation of postsynaptic glutamate receptor lead to influx of lethal amount of Ca2+ into neurons.
GABA synthesis
Decarboxylation of glutamate using GAD (found exclusively in GABAergic neurons). GABA shunt describes the process of recycling GABA
GABA inactivation
Reuptake via GABA transporter (GAT)
Benzodiazepine
Sedative effect by increasing affinity of GABA to its receptor. Similar effect to alcohol.
Which neurotransmitters synthesis requires vitamin B12?
vitamin B12 requirement for choline synthesis may contribute to the neurologic symptoms of vitamin B12 deficiency.
Ach inactivation
Acetylcholine esterase (ACE)
Hemicholinium
Choline, Ach substrate, is actively transported into presynaptic nerve terminal by Na- choline transporter (CHT), which can be blocked by the drug hemicholinium.
Vesamicol
Blocks VAT from transporting Ach into vesicles
Nicotinic receptors are …
Ionotropic
Muscarinic receptors are…
Metabotropic
What is the special feature of generalized muscle weakness in NMJ patients?
Muscle weakness begins in smaller muscles, thus the first symptom is often droopy eyelids (ptosis).
Alpha neurotoxin e.g. cobra, banded krait
They bind to nAChR, preventing Ach from binding to it.
Curare
Blocks NMJ, causing gradual total paralysis including respiratory.
Non-depolarizing neuromuscular blocking agents (NMBAs)
-curium, -curonium (same mechanism as curare)
prevents Ach from binding to nAchR
depolarizing neuromuscular blocking agents (NMBAs) e.g. succinylcholine
Causes continuous depolarization, until the gates are maintained in inactivation state.
This is called the DEPOLARIZATION BLOCK.
What is the clinical difference in depolarizing neuromuscular blocking agents (NMBAs) and non-depolarizing neuromuscular blocking agents (NMBAs)?
depolarizing neuromuscular blocking agents (NMBAs) will also have muscle fasciculations
What is the classical presentation of MG?
Decremental response on repetitive nerve stimulus (RNS).
Common underlying causes behind MG
Thymoma, thyroid diseases produce AchR Ab which bind to and cause nAchR dysfunction.
How can we test for MG without tools?
Asking the patient to look up continuously will cause the patient’s eyelids to droop further.
Pyridostigmine
Acetylcholinesterase inhibitor
Ice pack test
Diagnostic test for MG
Abdominal pain, profound sweating, diarrhea, excessive salivation, lacrimation, urinary incontinence and generalized weakness. Further examination will also show …
Bradycardia, bilateral miosis, hyperactive bowel sound, and muscle fasciculation.
The patient likely has an excess of Ach inhibitor or ingested insecticide.
Organophosphate
Binds to and inactivates AchE
Symptoms: SLUDGE - M (muscarinic effect of nAchR)
Salivation
Lacrimation
Urinary incontinance
Diarrhea
Gastric pain
Emesis
Miosis
Nicotinic effect: muscle fasciculation and weakness
Nerve gas Sarin
organophosphorus compounds
Alzheimer’s disease
Basal forebrain and brainstem cholinergic system atrophy. Symptomatic relief can be given using AchE inhibitors e.g. Rivastigmine, Donepezil, Galantamine. The effect is not sustained.
catecholamines
Dopamine, NorE, E
Catecholamine precursor
Tyrosine, can be synthesized from Phe in the liver
What vitamin is needed to synthesize Dopamine?
Vitamin B6
What vitamin is needed to turn NorE into E?
SAM B12, folate
Inactivation of Catecholamine
MAO (monoamine oxidase) more abundant in neuron
COMT (Catechol-O-methyltransferase) more abundant outside of NS
What is the endproduct of dopamine?
Homovanillic acid (HVA)
What is the endproduct of NE?
Vanillylmadelic acid (VMA)
Serotonin (5-HT) precursor
Tryptophan via LNAT
Serotonin inactivation
MAO
Dopaminergic projections
- Nigrostriatal pathway
- Mesolimbic & mesocortical pathway
- Tuberoinfundibular pathway
Nigrostriatal pathway
Initiates & maintains Motor behaviors: from substantia nigra to caudate and putamen
Mesolimbic and mesocortical pathway
From ventral tegmentum to amygdala, hippocampus, nucleus accumbens, septal area, and frontal cortex.
Initiates & maintains Goal-directed and reward-mediated behaviors
D1 receptor
Increased cAMP, stimulation of postsynaptic cell
D2 cell is the opposite effect
Carbidopa, Benserazide
Prevents levodopa from being synthesized into dopamine outside of the brain. Cannot follow into the brain.
How do anticholinergics (muscarinic receptor antagonists) relieve parkinsonism?
Dopamine is normally inhibitory towards Ach release, which results in smooth motor behavior. Anticholinergics helped relieve symptoms by preventing this excess of Ach from binding to mAchR.
Schizophrenia cause
Excessive dopamine in mesolimbic pathway. This causes hallucinations, delusions, and disorganized thought.
Antipsychotic drug mechanism
D2 antagonist in mesolimbic pathway.
This has the adverse effect of “Drug-induced parkinsonism”, which is why anticholinergics is often given in tandem to reduce these side effects.
Noradrenergic projections
Locus ceruleus:
Attention, Arousal, Vigilence
Pain modulation
Cheese reaction
Tyramine is normally degraded by MAO. Patients on MAO inhibitors, e.g. selegiline, rasagiline, cannot eat cheese because they will cause catecholamines to leak into the circulation and cause extensive symp activation and potential death.
