13. Noradrenergic neurotransmission Flashcards
What does the chemical group that monoamin neurotransmitters belong to?
One aminogroup derived from aromatic amino acids through decarboxylation
What are 2 examples of monoamine neurotransmitters groups?
1/ Catecholamines
2/ Indolamines
What are some examples of Catecholamines?
1/ noradrenaline/norepinephrine (adrenaline/epinephrine)
2/ dopamine
What is an example of Indolamines?
serotonine
What is the structure of Cathecholamines
cathecol (benzene diol) plus amine-containing side chain
What are Cathecholamines synthesized from?
They are synthesized from tyrosine (phenylalanine)
What are some chemical characteristics of Cathecholamines?
poorly absorbed and are degraded in the stomach can not cross the blood brain barrier
Where can you find Noradrenaline - norepinephrine (neurotransmitter)?
– brain
- postganglionic sympathetic neurons
- small amount in the circulation as a hormon
Where can you find Adrenaline - epinephrine (hormone)?
- from the adrenal medulla
- in small portion of neurons in the central nervous system
Where can you find Dopamine (neurotransmitter)?
– brain modulator
– in the periphery (kidney)
Identify this molecule
L-DOPA
=> 3,4-Dihydroxy-L-phenylalanine
Identify this molecule
Dopamine
-> 3-4-dihydroxy-phenethylamine
Identify this molecule
Noradrenaline – norepinephrine
Identify this molecule
Adrenaline – epinephrine
Tyrosine synthesis
-> Identify this molecule
5,6,7,8 - Tetrahydrobiopterin
Tyrosine synthesis
-> Identify 1 & 2
1/ Dihydrobiopterin reductase
2/ Phenylalanine hyroxylase
What are the consequences of tetrahydrobiopterin deficiency?
Dopamine
Noradrenaline
Serotonine
Tyrosine synthesis
-> What are consequences of PAH deficiency?
classic PKU
1:8000-9000
phenylpyruvate, phenyllactate
phenylacetate
Therapy: diet
What are Amino acid derivatives?
-> What is the role of Tyrosine hydroxylase?
Tyrosine hydroxylase can catalyse phenylalanine
➔ tyrosine conversion
What is the enzyme involving in melanin synthesis?
melanocyte specific copper-dependent tyrosinase
Noradrenergic synapse
-> What is the role of AMPT?
It inhibits tyrosine hydroxylase and norepinephrine synthesis
(AMPT (alpha-methyl-para-tyrosine) is an inhibitor of tyrosine hydroxylase, the rate-limiting enzyme in dopamine biosynthesis.)
Noradrenergic synapse
-> What is the role of Reserpine?
It inhibits VMAT (Vesicular monoamine transporter) and depletes norepinephrine stores
Noradrenergic synapse
-> What is the role of NRI?
Antidepressant that inhibit the norepinephrine transporter (same with SNRI)
Noradrenergic synapse
-> What is the role of SNRI?
Antidepressant that inhibit the norepinephrine transporter (same with NRI)
Noradrenergic synapse
-> What is the role of Tropolone?
It inhibits COMT
(Catechol-O-methyltransferase is one of several enzymes that degrade catecholamines, catecholestrogens, and various drugs and substances having a catechol structure)
Noradrenergic synapse
-> What is the role of Prazosin?
An alpha-1 antagonist
Noradrenergic synapse
-> What is the role of MAOI?
An antidepressant inhibiting MAO(A)
(An enzyme called monoamine oxidase is involved in removing the neurotransmitters norepinephrine, serotonin and dopamine from the brain.)
Noradrenergic synapse
-> What is the role of Yohimbine?
What is an alpha 2 antagonist
Noradrenergic synapse
-> What is the role of Propranolol?
a Beta antagonist
Synthesis of Dopamine
Synthesis of Noradrenaline
Synthesis of Adrenaline
What is tyrosine hydroxylase?
a mixed function oxygenase (monooxygenase)
Rate limiting enzyme. (Catecholamines: negative feedback)
Activation by Ca2+ (Ca2+/calmodulin-dependent kinase)
During increased sympathetic activity – increased tyrosine hydroxylase activity
What is the role of L-DOPA in therapy?
Parkinson’s disease
The role of Dopa-decarboxylase inhibitors?
L-DOPA → Parkinson’s disease
The role of α-metil-DOPA inhibitors?
α-metil-DOPA → hypertension therapy (α2-receptor-agonist)
Uptake of norepinephrine/epinephrine/dopamine into synaptic vesicles
-> Characteristics of VMTA 2 (VMAT: vesicular monoamine transporter)
VMTA 2 (VMAT: vesicular monoamine transporter)
vesicular membrane transporter 2
(-12 transmembrane domain)
NE -broad substrate-specificity to E biogenic amines
DA (triptamine, tiramine, amfetamin – compete with endogenous catecholamine)
(-high affinity for reserpine irreversible inhibitor
– depletion of vesicles)
(-altered VMTA2 expression in bipolar disease
(lithium influences)
Uptake of catecholamines by presynaptic terminals
- Active transport
- Na+ cotransport (secondary active transport)
- Sustained depolarization
*→ reverse function
What are Inhibitors for Uptake of catecholamines by presynaptic terminals?
Cocain
tricyclic antidepressant
Relative harmfulness of drugs
-> The role of cocaine?
inhibits noradrenaline, dopamine serotonine reuptake
What happen during Cocaine intoxication?
Alpha and beta adrenerg receptor stimulation
Hypertension, tachycardia, chest pain Agitated, tremulous
Treatment: benzodiazepines
Treatment for cocaine intoxication
benzodiazepines
What is The mode of action of amphetamine?
an indirectly acting sympathomimetic amine: Non-exocytotic release of NA
What happen during Non-exocytotic release of NA?
NA release, MAO – monoamine oxidase inhibitor, NET inhibitor,
Catabolism of catecholamines
-> most of the released noradrenaline recaptured by ____
NET (Sodium- dependent noradrenaline transporter SLC6A2)
(MAO – monoamine oxidase
COMT – catechol oxymethyl transferase)
Describe Catabolism of catecholamines?
(MAO A) in the gastrointestinal tract and liver – prevents access of ingested indirectly acting amines (e.g. tyrosine➔tyramine) to the general circulation
Patients on monoamine oxidase inhibitors (especially MAO-A inhibitors or non- selective MAO inhibitors) are advised to avoid ___ (what food?)
tyramine rich foods.
Name of a MAO – monoamine oxidase inhibitor?
Cigarette smoke
What are the 2 Enzymes in the metabolism of noradrenaline?
MAO – monoamine oxidase
COMT – catechol oxymethyl transferase
The role of MAO – monoamine oxidase
oxidative deamination of catecholamines (adrenaline, noradrenaline, dopamine, serotonine)
The role of COMT – catechol oxymethyl transferase
COMT: methyl transfer to the 3-hydroxy group on the ring from S-adenosylmethionine (SAM)
(adrenaline, noradrenaline, dopamine)
(multiple location: brain, liver, kidney)
What is Pheochromocytoma?
Most common tumor of the adrenal medulla in adults Derived from chromaffin cells
Most tumors secrete epinephrine, norepinephrine, and dopamine, which can cause episodic hypertension.
Episodic hyperadrenergic symptoms (5 P’s):
Pressure (high BP)
Pain (headache)
Perspiration
Palpitations (tachycardia)
Pallor
Therapy for Pheochromocytoma
α antagonist (non-selective, irreversible)
Surgery
The main pathways of noradrenaline metabolism
-> Identify 1 - 2
1/ VMA: Vanillin-mandulasav
2/ MPHG
The main pathways of noradrenaline metabolism
-> Identify 1 - 2
1/ NM: normetanephrine
2/ NA: noradrenaline
The main pathways of noradrenaline metabolism
-> Identify enzyme a & b
The main pathways of noradrenaline metabolism
-> Identify enzyme a & b
a/ AR: Aldehyde reductase
b/ ADH: aldehyde dehydrogenase
For the synthesis of dopamine, epinephrine and norepinephrine
-> which reaction is the rate-limiting step?
The synthesis of DOPA from Tyrosine
-> catalyzed by tyrosine hydroxylase
How can step 1 be activated?
activation by phosphorylation: Ca2+/calmodulin-dependent kinase PKA, PKC, PKG
The main pathways of noradrenaline metabolism
-> What is the synthesis location of Dopamin
Cytosol
The main pathways of noradrenaline metabolism
-> What is the synthesis location of Epinephrine
Cytosol
The main pathways of noradrenaline metabolism
-> What is the synthesis location of Norepinephrine
Synaptic vesicles
The adrenal medulla releases ___ and ____ into the bloodstream
epinephrine (adrenaline) and norepinephrine (noradrenaline)
Cellular view of catecholamine synthesis.
-> ____ synthesizes and stores epinephrine in a sequence of four enzymatic and three transport steps
The chromaffin cell
Cellular view of catecholamine synthesis. The chromaffin cell synthesizes and stores epinephrine in a sequence of four enzymatic and three transport steps
-> What are they?
AADC, amino acid decarboxylase; DA, dopamine; DBH, dopamine b-hydroxylase; Epi, epinephrine; NE, norepinephrine; TH, tyrosine hydroxylase.
