Chemical And Biochemical Basis Of Neurotransmission Flashcards
5 steps of chemical communication
1) Signal produced and released
2) signal is received
3) signal transmission and amplification occurs
4) cellular response occurs in target
5) signal termination
- occurs at any of the previous 4 steps
Which are classical neurotransmitters?
Acetylcholine
Amino acids (note: these DONT cross BBB)
- glutamate
- aspartate
- GABA
- Glycine
Amines
- catecholamines
- serotonin
- histamine
all are small molecules
What are non classical neurotransmitters?
Opioids (neuropeptides)
Tachyknins (neuropeptides
Nitric oxide
Lipids
How are amino acids used?
1) generate body proteins
2) generate Nitrogen containing compounds
- hormones
- purines
- Pyrimidines
3) broken down to urea and excreted
4) catabolism by other metabolic processes
The BBB transport mechanisms
1) Simple diffusion
- water
- oxygen
- CO2
- non-polar drugs
2) facilitated diffusion vis specific transporters
- glucose (via GLT-1 (endothelial cells) or GLT-3 (neurons))
- essential FA’s only
- monocarboxylic acids (lactate, acetate, pyruvate, ketones)
- large neutral AAs
- vitamins
3) receptor-mediated
- insulin
- transferrin
- IGFs
Specific characteristics of the BBB
1) possess very tight junctions between endothelial cells
2) narrow intercellular spaces
3) lack pinocytosis in cells
4) continuous basement membrane
5I) astrocytes extension
How are large neutral AAs transported into the BBB and what AAs does this constitute?
Phe, Leu, Tyr, lle, Val, Trp, Met, His
Use the L-system AA transporter to get above AAs in and out of the BBB
5 steps of chemical neurotransmission
1) Synthesis of the neurotransmitter in the presynaptic neuron
2) Storage in presynaptic nerve terminal
3) release of the neurotransmitter into synaptic cleft
4) binding and recognition of neurotransmitter by receptors
5) termination of the action
Steps of synaptic neurotransmission
1) action potential depolarizers presynaptic terminal membrane and Ca2+ rushes into the synaptic terminal
2) Ca2+ ions in terminal promote fusion of vesicular and terminal membranes, allowing neurotransmitters to release into synaptic cleft
3) neurotransmitter binds with receptor on channels across synaptic cleft and opens, allowing Na+ to rush into post synaptic neuron and excite it.
* cycle 1-3 is repeated until target organ is reached*
What enzymes generate acetylcholine and catabolism it
Generate = choline acetyltransferase (ChAT)
Catabolism = Acetylcholinesterase (AChE)
acetyl CoA (glucose byproduct) + choline (essential protein) -> acetylcholine
How is AChE inhibited?
1) Military nerve gases (sarin/tabun/soman)
2) Green mamba snake venom
3) Donepezil (aricept) medications
How are glycine, GABA, glutamine and aspartate all produced
Glycine
- serine -> glycine via folate enzyme
Aspartate
- Oxaloacetate -> Aspartate via aminotransferase/ pyridoxal phosphate (PLP) enzyme
Glutamate
- A-ketoglutarate -> glutamate via aminotransferase/ PLP anime
GABA
- Glutamate -> y- aminobutyric acid (GABA)
How is PLP dervived?
From vitamin B6 and enzymes that require zinc to synthesis
- deficiencies in either of these vitamins can lower the generation of PLP and consequently aspartate/glutamate/GABA
Clinical correlates assocaited with GABA
Huntington’s
Parkinson’s
- insufficient dopamine-producing cells
Senile dementia
Alzheimer’s
Schizophrenia
Epileptic seizures
- treated with Valproic acid since it inhibits GABA transaminase and causes increase GABA production
CLincial correlates associated with aspartate and glutamate
Excitotoxicity
- leads to neuron death
ALS
Alzheimer’s
Clinical correlates related to glycine
Hyper glycinemia
- leads to lethargy and mental retardation
How are catecholamines synthesized and degraded?
Synthesis
- tyrosine -> Dopamine/ NE/epinephrine
- uses tyrosine hydrooxylase enzyme to produce dopamine which in turn can make NE/epinephrine via ascorbate and SAM enzymes respectively
Termination
- MAO and COMT enzymes
- MAO reuptakes back into presynaptic neruon and destroys in terminal
- COMT takes into effector cell and degrades there
- both also degrade catecholamines in liver*
epinephrine and NE also act as hormones and are synthesized outside CNS in adrenal medulla
Coenzyme/cofactors required to generate Catecholamines
PLP
Tetrahydrobiopterin (BH4)
Ascorbate (Vit. C)
Copper
What are the final metabolites for norepinephrine and epinephrine and dopamine
NE/epinephrine
= vanillylmandelic acid (VVA)
Dopamine
= homovanillic acid (HVA)
How is serotonin synthesized and degraded?
Synthesis
- uses tryptophan as precursor
- uses PLP and BH4 cofactor to generate
Degradation
- MOA enzyme
What are functions of serotonin?
CNS: pain/regulation of sleep/appetite/ body temp/ blood pressure/ mood
PNS: neural reflexes/intestinal secretion/ motility
Pineal gland: precursor for melatonin
How is histamine synthesized and degraded
Synthesized
- uses Histidine
- requires PLP coenzyme
Degraded
- MAO-B enzyme
- DOES NOT CROSS BBB*
How are neuropeptides synthesized and degraded
Synthesized:
- transcription/translation in rER
- packaged into golgi vesicles
Termination
- degraded by peptidases in the CNS
Functions:
- sleep/hunger/compassion/stress
Nitric oxide synthesis and degradation
Synthesis
- nNOS (nitric oxide synthase)
Degradation
- naturally through lungs and kidneys
- is a retrograde messenger in the CNS *
Nitric oxide isoform
1) nNOS
- dependent on calcium
- constitutive expression
- found in CNS/PNS
2) iNOS
- NOT dependent on calcium
- inducible only by cytokines
- found in macrophages and immune cells
3) eNOS
- dependent on calcium
- constitutive expression
- found in endothelial cells
