NORADRENALINE: SYNTHESIS, STORAGE, RELEASE, FATE & METABOLISM Flashcards
How is cholesterol produced in the adrenal cortex
• Cholesterol-processing enzymes in sER, inner mitochondria membrane
– Tubulovesicular mitochondria.
• Much inner membrane surface area
• MuchP450s
• Parenchymal cells can produce cholesterol de novo
– Mainly endocytosis of LDL
– Cholesterol-rich lipid droplets in cytoplasm
• Capsule + 3 cell layers
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What cells of the adrenal cortex can produce cholesterol de novo
Parenchymal cells can produce cholesterol de novo
– Mainly endocytosis of LDL
– Cholesterol-rich lipid droplets in cytoplasm
What’s the adrenal cortex made of
Capsule + 3 cell layers
What part of the adrenal half is a modified sympathetic ganglion
Adrenal medulla
Function of adrenal medulla
– Release catecholamines to ECF
Describe the cells of the adrenal medulla
They’re called pheochromocytes
– Axonless secretory cells
– Two cell subpopulations
• Same cell population under different physiologic states – Concent cortisol exposure
• Norepinephrine (noradrenaline) producing cells
• Epinephrine (adrenaline) producing cells
How do pheochromocytes exceed their cells to the ECF
Secrete products from granulesECF by exocytosis
Does the adrenal medulla contain post ganglionic fiber
• Adrenal medulla is a modified part of sympathetic nervous system
– Modified sympathetic ganglion that does not give rise to postganglionic fibers
What stimulates the release of the medullary hormones into the circulation
– Stimulation of preganglionic fiber prompts secretion of hormones into blood
•About. 20% of hormone release is norepinephrine
•About 80% of hormone released is epinephrine(adrenaline)
Describe the similarities between a normal sympathetic ganglion and an adrenal medulla
In a normal sympathetic ganglion, at the pre synaptic cleft, Ach is produce and the. At the post ganglionic cleft, Epinephrine and norepinephrine are produced
But In the adrenal medulla, the presynaptic ganglion brings Ach into the medulla where Epinephrine and norepinephrine are produced, in the absence of moving to a post synaptic cleft, the catecholamimes are secreted into the ECF directly
What’s the primary stimulus for increased adrenomedullary secretion
Stress
Epinephrine and norepinephrine are released into the ECF by exocytosis of what granules
– Secreted into blood by exocytosis of chromaffin granules
What are the functions of epinephrine
– Maintenance of arterial blood pressure
– Increases blood glucose and blood fatty acids
What’s the stimulus for Epinephrine secretion
Stress (psychological reactions), elevated sound levels, intense light, low blood sugar levels
Describe the synthesis of epinephrine
Tyrosine
|Tyrosine hydroxylase
|
DOPA
|DOPA decarboxylase
|
Dopamine
|Dopamine B hydroxylase
|
NE
|PNMT
|
Epinephrine
Conc of L-dopa in the plasma
1-1.5 mg/dL
How is L- Dopa transferred into cells
Active transport into cells
How many enzymes convert L-Dooa into epinephrine
4 enzymes
What’s the plasma ratio of norepinephrine to epinephrine
ratio 8:2
Explain the conversion of tyrosine to adrenaline
Phenylalanine
| phenylalanine hydroxylase
|
Tyrosine
|tyrosine hydroxylase
|
L Dopa
|Dopa decarboxylase
|
Dopamine
|Dopamine B hydroxylase
|
Norepinephrine
|phenylethanolamine N methyltransferase
|
Epinephrine
I’m what step of the synthesis of epinephrine is tetrahydrobiopterin (O2) converted to dihydobiopterin (H2O)
Tyrosine to L Dopa (tyrosine hydroxylase)
In what step in the synthesis of epinephrine is S-adenosylhomocystein converted to S-adenosylmethione
Norepinephrine to epinephrine (phenylethanolamine N methyl transferase)
What’s the % to which catecholamines are produced
Epinephrine 80%
Norepinephrine 20%
What are the adrenergic receptors
• α1β1: excitatory
• α2β2: inhibitory
What’s the location of the alpha 1 receptor
Most synaptic target cells
What’s the location of the alpha 2 receptor
Digestive system
What’s the location of the beta 1 receptor
Heart
What’s the location of the beta 2 receptor
Skeletal muscle
Smooth muscle of some blood vessels
Organs
What has more affinity for alpha 1 receptor
NE
What has more affinity for alpha 2 receptor
NE
What has more affinity for beta 1 receptor
NE and Epinephrine
What has more affinity for beta 2 receptor
Epinephrine
What type of response is elicited from the alpha 1 receptor
Generalised arteriolar constriction
What type of action is elicited by the alpha 2 receptor
Decreased motility of the digestive tract
Hat kind of action is elicited by the beta 1 receptor
Increased rate and strength of cardiac cells
What kind of action is elicited by the Beta 2 receptor
Breakdown of glycogen in skeletal muscle
Bronchioles dilation and arteriolar vasodilation in skeletal muscle and heart
(Decreased smooth muscle constriction)
What’s the function of tyrosine hydroxylase
Ring hydroxylation to L-DOPA (L-Dihydroxy-PhenylAlanine)
What cofactor does tyrosine hydroxylase contain
Contains Fe2+; tetrahydrobiopterin cofactor
What regulates tyrosine hydroxylase
Activity regulated by preganglionic nerves
– Get phosph’n PKA, PKC and calmodulin-dependent kinases
What’s the long term stimulation of tyrosine hydroxylase
upregulation of transcription, translation
What inhibits the production of tyrosine hydroxylase
Increased L-DOPA
What’s another name for Dopa decarboxylase
L-aromatic amino acid decarboxylase
What’s the go factor for DOPA decarboxylase
Pyridoxal phosphate cofactor
Where is The DOPA decarboxylase end product found
In the CNS
Where is DOPA decarboxylase stored and how is it released
• Stored in secretory vesicles
– Enter by active transport
– MVATs (Vesicular MonoAmine Transporters)
What provides the side chain hydroxylation to become noradrenaline
3) Dopamine beta Hydroxylase
What cofactors do dopamine beta hydroxylase contain
Contains Cu; Vit C cofactor
Where does the reaction of dopamine bet hydroxylase occur
• Rxn w/in secretory vesicle
Where does the action of dopamine beta hydroxylase take place
• Rxn w/in secretory vesicle
Where is the end product of dopamine beta hydroxylase
• End prod in symp. nerves, most central catecholaminergic neural tracts
What’s the function of Phenylethanolamine N- MethylTransferase (PNMT
N-methylation to epinephrine
What’s the S donor for phenylethanolamine N methyl transferase
S- Adenosylmethionine
Where does the action of phylehanolamine N methyl transferase occur
Cytoplasm
What happens to norepinephrine and epinephrine after the action of phenylethanolamine n methyl transferase
– Norepinephrine leaves vesicle
• Passive transport
• Concent gradient
– Epinephrine must reenter secretory vesicle
• Active transport
What does the expression of PNMT depend on
• Expression depends on high local cortisol
– From adrenal cortex
– Through sinusoid system
Explain Transcriptional activation of PNMT
Transcriptional activation of PNMT gene through ligand-activated glucocorticoid receptor
– Also other transcription factors
What stimulates PMNT
Glucocorticoids
What’s the effect of adrenaline on PMNT
Feedback inhibition
What other places can PMNT be found
Other than adrenal medulla
kidney, lung, pancreas
Function on non specific NMT
Contributes to peripheral conversion norepi. to epi.
Where are cathecolamine stored
Secretory vesicles
How are cathecholamines transported
Active transport via VMATs
– ATP-driven proton pump
– In vesicle membranes
– pH, electrical gradient
– Antiporte
What are the 12 transmembrane helical segments found in secretory vesicles
Related to plasma membrane monoamine transporters
How are Ach released from presynaptic ganglion
Nicotinic receptors
Get depolarization of pheochromocytes
act’n voltage-gated Ca2+ channels influx Ca2+
exocytosis of secretory vesicles
• Chromogranins, DBH, ATP, other peptides released
What other things are realeased at the presynaptic vesicle along with Ach
Chromogranins, DBH, ATP, other peptides released
What can cathecolamine not penetrate
• BBB
• Fetus
How does fetus get catecholamines
Fetal production (mostly norepi) through fetal zone
• Impt in intrauterine life (cardiovascular responses)
• Large
• Placenta expresses catecholamine degrading enzymes
What catecholamine is more in featal life
NE
How does NE get degraded I’m featal life
Placental norepi. transporter
– Delivers circulating fetal catechol’s for degrad’n
What’s the half life of catecholamines
• Short-lived molecules
– 10 sec to 1.7 min
What are most catecholamines associated with
• 50-60% associated with albumin
How are catecholamines eliminated
– At synapse, ISF near sympathetic neurons
• Reuptake into nerve terminals
• Reenter vesicles via VMAT OR
• Become degraded by monoamine oxidase (MAO, MAOIs bind to MAO for inhibition)
– In target cells
• Degraded by Catechol-O-MethylTransferase (COMT)
– 5% directly filtered into urine
When epinephrine is acted upon by COMT, what does it become
(At the target site)
It becomes metanephrine
Then becomes metanephrine sulfate or glucoronide
Where does MAO degrade catecholamine
At the synapse
Where does COMT degrade catecholamine
At the target site
When MAO acts of epinephrine, what does it become
(At the synapse)
3,4 dihydroxy mandelic acid
How is 3,4 dihydroxymandelic acid degraded
Acted on by COMT to give 3, methoxy 4, hydroxymadelic acid
aka vanillymandelic acid
How else can 3, methoxy 4, hydroxy mandelic acid (vanillymandelic acid) be gotten other than degradation of 3,4 dihydroxymandelic acid ( by COMT)
By degradation of metanephrine by MAO
How do you remember the break down of epinephrine and where each enzyme works on
On a straight line(vertically) it’s worked on by COMT (at target site)
So from epinephrine to metanephrine
And from 3,4 dihydroxymandelic acid to 3,methoxy 4, hydroxylase mandelic acid
Are both by COMT
By on a horizontal line, it’s by MAO (at synapse)
So from epinephrine to 3,4 dihydroxymandelic acid
And from metanephrine to 3, methyl 4 hydroxymandelic acid
Are both by MAO
Where is MAO found
Outer mitochondrial membrane
What are the substrates of MAO
also include serotonin, histamine
How does MAO work
Oxidizes amino grp to aldehydes
– Further oxidation by nonspecific aldehyde dehydrogenase
What is the ultimate product of MAO
Ultimate production of dihydroxymandelic acid (DOMA)
What are the types of MAO
– MAO-A and MAO-B
What kind of degradation does COMT do
extraneuronal degradation
What is the methyl donor for COMT
S-Adenosyl methionine
What kind of catecholamine is COMT important for degrading
Important to circulating catecholamines
How does catecholamine get its final conjunction
Sulfate, glucuronate in liver, gut
– Excretion through urine
What are the sympathoadrenal functions
1) Catecholamines regulate intermediary metabolism.
- Carbohydrate metabolism (β-AR ): blood glucose levels increased
- Fat metabolism (β-AR ): activates a hormone-sensitive lipase, triglyceride lipasemetabolizes fats into fatty acids (FFAs) and glycerol
- Protein metabolism (β-AR ): decreases the release of amino acids from skeletal muscle
2) The sympathetic nervous system regulates thermogenesis.
- Shivering thermogenesis:
- Nonshivering (chemical) thermogenesis: brown adipose tissue in the rat
3) Adrenergic receptors mediate cardiovascular responses to stress (β-AR )
4) physiologic implications
What are the physiological implications of the sympathoadrenal catecholamines
• General: activates fight/flight mechanisms. – Mobilizes energy, redist’s blood
• Opposes parasympathetic system
– Promotes digestion, storage of energy
– BUT distinct target cell pop’ns w/in organs
• Many targets; overall
– Increase cardiac output, blood pressure
– Bronchodilationmatched perfusion w/ increased ventilation
– Blood diverted from viscera and skin to muscle
• Retain blood to brain
– Mobilize fuel from energy stores
Is PNMT Involved in the synthesis of NE
No
Where is PNMT found
Adrenal medulla
How is NE stored
In vesicles carried by VMAT
What synthesis of Epinephrine occurs before entry into the vesicles
Tyrosine - - - - -> Dopamine
What synthesis of epinephrine occurs in the vesicles
Dopamine’s.- - - - - -> Epinephrine
Describe the release of Epinephrine
• AP goes through the membrane
• Once AP gets to the axon, it opens up Ca2+ gated channels and causes an influx
• The excess Ca2+ pulls the vesicle to the end of the membrane
The vesicle fuses to the membrane, exocytosis occurs and Epinephrine is released
How does Epinephrine carry out its functions
By binding to adrenergic receptors
Describe the metabolism of epinephrine
It either goes back into the neuron(reuptake) and metabolized by MAO
Or it’s metabolized by COMT at the liver(target organ)
What drug inhibits the synthesis of Epinephrine
Methyl tyrosine inhibits conversion of tyrosine to DOPA
What inhibits the storage of epinephrine
Reserpine blocks VMAT from taking epinephrine
What blocks the release of epinephrine
Guanethidine and Bratylium
What stimulates the release of epinephrine
Amphethamine
What inhibits the metabolism of epinephrine
MAOI
And COMT Inhibitors
What inhibits the reuptake of NE
Cocaine
Tricyclic antidepressants
