Everything about Noradrenaline totally explained
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Norepinephrine (
INN) (abbreviated
norepi or
NE) or
noradrenaline (
BAN) is a
catecholamine with dual roles as a
hormone and a
neurotransmitter.
Norepinephrine is synthesized from
dopamine by
dopamine β-hydroxylase. It is released from the
adrenal medulla into the blood as a
hormone, and is also a
neurotransmitter in the
central nervous system and
sympathetic nervous system where it's released from noradrenergic
neurons. The actions of norepinephrine are carried out via the binding to
adrenergic receptors.
As a
stress hormone, norepinephrine affects parts of the brain where
attention and responding actions are controlled. Along with
epinephrine, norepinephrine also underlies the
fight-or-flight response, directly increasing
heart rate, triggering the release of
glucose from energy stores, and increasing blood flow to
skeletal muscle.
However, when norepinephrine acts as a
drug it'll increase
blood pressure, triggering a compensatory
reflex that overcomes its direct stimulatory effects on the heart. The reflex, called the
baroreceptor reflex, results in a drop in heart rate called
reflex bradycardia.
Origins
Norepinephrine is released when a host of
physiological changes are activated by a stressful event.
In the brain, this is caused in part by activation of an area of the
brain stem called the
locus ceruleus. This nucleus is the origin of most norepinephrine pathways in the brain. Noradrenergic neurons project bilaterally (send signals to both sides of the brain) from the locus ceruleus along distinct pathways to many locations, including the
cerebral cortex,
limbic system, and the
spinal cord, forming a
neurotransmitter system.
Norepinephrine is also released from
postganglionic neurons of the
sympathetic nervous system, to transmit the
fight-or-flight response in each tissue respectively. The
adrenal medulla can also be counted to such postganglionic nerve cells, although they release norepinephrine into the blood.
Norepinephrine system
The noradrenergic neurons in the brain form a
neurotransmitter system, that, when activated, exerts effects on large areas of the brain. The effects are alertness and
arousal, and influences on the
reward system.
Anatomically, the noradrenergic neurons originate both in the locus coeruleus and the lateral tegmental field. The axons of the neurons in the locus coeruleus act on
adrenergic receptors in:
On the other hand, axons of neurons of the
lateral tegmental field act on
adrenergic receptors in
hypothalamus, for example.
This structure explains some of the clinical uses of norepinephrine, since a modification of the system affects large areas of the brain.
Mechanism
Norepinephrine is synthesized from tyrosine as a precursor, and packed into synaptic vesicles. It performs its action by being released into the synaptic cleft, where it acts on adrenergic receptors, followed by the signal termination, either by degradation of norepinephrine, or by uptake by surrounding cells.
Biosynthesis
Norepinephrine is synthesized by a series of enzymatic steps in the
adrenal medulla from the
amino acid tyrosine:
The first reaction is the oxidation into dihydroxyphenylalanine (L-DOPA) (DOPA = 3,4-DiHydroxy-L-Phenylalanine), catalyzed by tyrosine hydroxylase. This is the rate-limiting step.
This is followed by decarboxylation into the neurotransmitter dopamine, catalyzed by pyridoxal phosphate & DOPA decarboxylase.
Last is the final β-oxidation into norepinephrine by dopamine beta hydroxylase, requiring ascorbate as a cofactor (electron donor).
Image:L-tyrosine-skeletal.png|Tyrosine
Image:Levodopa.png|Levodopa
Image:Dopamine_chemical_structure.png|Dopamine
Image:Noradrenaline_chemical_structure.png|Norepinephrine
Vesicular transport
Between the decarboxylation and the final β-oxidation, norepinephrine is transported into synaptic vesicles. This is accomplished by vesicular monoamine transporter (VMAT) in the lipid bilayer. This transporter has equal affinity for norepinephrine, epinephrine and isoprenaline.
Release
To perform its functions, norepinephrine needs to be released from synaptic vesicles. Many substances modulate this release, some inhibiting it and some stimulating it.
For instance, there are inhibitory α2 adrenergic receptors presynaptically, that gives negative feedback on release by homotropic modulation.
Receptor binding
» Further reading: Adrenergic receptor
Norepinephrine performs its actions on the target cell by binding to and activating adrenergic receptors. The target cell expression of different types of receptors determines the ultimate cellular effect, and thus epinephrine has different actions on different cell types.
Termination
Signal termination is both a result of degradation and reuptake.
Degradation
In mammals, norepinephrine is rapidly degraded to various metabolites. The principal metabolites are:
Normetanephrine (via the enzyme catechol-O-methyl transferase, COMT)
3,4-Dihydroxymandelic acid (via monoamine oxidase, MAO)
3-Methoxy-4-hydroxymandelic acid (via MAO)
3-Methoxy-4-hydroxyphenylglycol, "MHPG" (via MAO)
Epinephrine (via PNMT)
Uptake
Uptake is either done presynaptically (uptake 1) or by non-neuronal cells in the vicinity (uptake 2).
Further Information
Get more info on 'Noradrenaline'.
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