Sympathetic Mechanisms Flashcards
The ANS innervates all tissues, except what?
skeletal muscle
What do the pre-ganglionic and postganglionic neurons of the sympathetic nervous system release?
Preganglionic: acetylcholine
postganglionic: noradrenaline
The preganglionic neuron leaves the spinal cord at…
the thoracic or lumbar region (T1-L3)
Which is why the sympathetic nervous system is also known as the thoracolumber system
Where are ACh receptors are located?
The ACh receptors are located on postganglionic nicotinic fibres
What is the criteria for a neurotransmitter?
1.Substance must be synthesized in the neuron
2. Enzymes and substrates for synthesis must be present in it
3. Substance must be present in the neuron.
4. Calcium dependant release
5. Exogenous synthetic neurotransmitter must mimic actions of true transmitter
6. There must be a mechanism for rapid termination of action
What are the steps in neurotransmission?
Synthesis
Storage
Release
Receptor-interaction
Inactivation
Re-uptake
Degradation
Discuss catecholamine synthesis
- It starts with tyrosine in the liver which is converted to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase enzyme (adding -OH)
But if tyrosine is deficient, synthesis can begin with phenyalanine, phenyalanine is converted to tyrosine by phenylalanine hydroxylase enzyme
- DOPA is converted to dopamine by DOPA decarboxylase (which removes -COOH)
- Dopamine is converted to Noradrenaline by dopamine beta hydroxylase (by removing -OH)
- Noradrenaline is converted to adrenaline by Phenylethanolamine N-methyl transferase enzyme (which adds a methyl group to the aliphatic chain)
Discuss neurotransmitter storage
- Dopamine is the first series of cathecolamines to be synthesized.
- It is the end product of synthesis of dopaminergic neurons in the central nervous system.
- Dopamine is actively transported to the active storage/resides as D-ß-H)
- Dopamine is rapidly converted to nor-adrenaline and catalyzed by the enzyme dopamine-ß-hydroxylase.
The enzyme is not specific and so requires
Cu2+ and ascorbic acid for its activity.
- In the chromatin tissue (Adrenal medulla) the enzyme phenylethanolalamine-N-
methyltransferase converts nor-adrenaline to adrenaline. - In the storage vesicles, there is Dopamine-B-hydroxylase, nor-adrenaline
What is the rate limiting enzyme and rate limiting step in caltecholamine synthesis?
Enzyme: tyrosine hydroxylase
Step: conversion of tyrosine to DOPA
Dopamine is synthesized in____whereas noradrenaline and adrenaline are synthesized______
Dopamine: Neuronal cytoplasm
NA and A: In the storage vesicle
Discuss release
- When actions potential hits the terminals calcium ion channels open
- Causing calcium influx
- Influx causes depolarization
Depolarization causes vesicles to move and fuse the membrane and released to synaptic cleft via exocytosis - Neurotransmitters binds to postsynaptic receptors (alpha and beta receptors)
5.This causes a cascade of events in the post-synaptic neuron leading to the effector organs carrying out their mode of action
Discuss inactivation
• High stores of NA competes for pterdine co-factor with tyrosine hydroxylase which results in decrease stores (depresses the activity) of tyrosine hydroxylase therefore NA will inhibit its own production (end product inhibition)
• The interaction of this is called end product inhibition. It simply means, it switches off the synthesis of nor-adrenaline when adequate stores of nor adrenaline is accumulated.
• Tyrosine hydroxylase is also inhibited by a-methyl phenylalanine and a host of other structurally related Cpds.
Meaning and Function of VMAT
Vesicle Monoamine transporting enzyme
Transport dopamine, and all the other enzymes needed for the conversion of dopamine to noradrenaline and noradrenaline adrenaline.
What are the re-uptake mechanisms and how are they carried out? Vesicular uptake is inhibited by what?
• The effect of nor-adrenaline is terminated by re-uptake of the large proportion of noradrenaline into:
I. Axon terminals (axonal uptake), This is called neuronal uptake 1
II. Re-uptake can be uptake into the parenchymal cells of the effector cells or organs. This is called extra neuronal uptake
III. Vesicular uptake: The membrane of intracellular vesicles has another amine pump the ‘vesicular monoamine transporter’ (VMAT-2), which transports catecholamines from the cytoplasm to the interior of the storage vesicle.
• The VMAT-2 transports monoamines by exchanging with H
• The vesicular NA is constantly leaking out into the axoplasm and is recaptured by this mechanism.
• This carrier also takes up ‘DA formed in the axoplasm for further synthesis to NA.
• This uptake is inhibited by reserpine, resulting in depletion of the catecholamines.
The neurotransmitter has been released to the synaptic cleft has to be taken up again, physiologically as you cannot continue to stay in the synaptic cleft, and it is taken up by re-uptake mechanism (axonal, extraxonal and vesicular)
Discuss degradation
There are 2 major enzyme involved in the breakdown of neurotransmitters:
monoamine oxidase (MAO) and Catechol-o-methyltransferase enzyme (COMT). This enzymes act in consent.
COMT requires Mg2+ or other divalent ions for its activities and it catalyzes the transfer of the methyl group from adenosine methionine to the free hydroxyl group of cathecholamines.
The methoxyl products are inhibitors of uptake 2, therefore they are pharmacological products to this effect.
After reuptake of NA Monoamine oxidase degrades NA
Also NA uptake isn’t the storage vesicle occurs by VMAT to be converted into
Some NA diffuses away by COMT (in the synaptic cleft)
And NA is converted to adrenaline by Phenylethanolamine N-methyl transferase
