Dopmaine pathways (finished) Flashcards
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Describe the structure of dopamine
catechol ring= 6 carbons
What are catecholamines?
= group of neurotransmitters which includes dopamine, noradrenaline + adrenaline
When was dopamine synthesised?
1910
Who were the 1st people to synthesise dopamine?
George Barger and James Ewens
What are catecholamines derived from?
tyrosine
What was dopamine initally considered to be?
a precursor to noradrenaline (norepinephrine) and adrenaline (epinephrine) with no function of its own
When was dopamine established as a neurotransmitter?
1958 but Nobel Peace prize won for this in 2000
Who established dopamine as a neurotransmitter with a function?
Arvid Carlsson
Describe the synthesis of dopamine
Synthesised in 2 steps:
- tyrosine hydroxylase (TH) converts tyrosine into L-DOPA by adding hydroxyl group (OH) to backbone of tyrosine- L-DOPA has short lifetime so is further converted by…
- DOPA decarboxylase- converts L-DOPA rapidly into dopamine by removing carboxyl group
What is considered to be the rate limiting step in dopamine synthesis?
= tyrosine hydroxylase
What is the difference between the enzymes involved in dopamine synthesis?
Tyrosine hydroxylase = substrate specific- only converts tyrosine
DOPA decarboxylase = non substrate specific- so can convert any L amino acid
What is the rate of dopamine synthesis regulated by?
Catecholamines can inhibit tyrosine hydroxylase (TH) found in cytosol
Describe 2 reasons why synthesis of dopamine is altered
- Presynaptic dopamine receptors (D2) inhibit synthesis and release of dopamine by activating signalling pathways- feedback inhibition which are negatively or positively coupled to cAMP signalling + Voltage gated calcium channels
- Neuronal activity alters synthesis = levels of activity of neurons can change amount of dopamine produced- more activity = more dopamine produced
Name a co-factor of tyrosine hydroxylase
Tetrahydrobiopterin (BH4) = crucial for correct function of tyrosine hydroxylase
Name 2 dopamine transporter proteins
DAT
VMAT
What is the structure of DAT and where is it located?
12 transmembrane-spanning protein ~619 amino acids- located on- pre-synaptic membrane
What is the main function of DAT?
Takes up excess dopamine from synaptic cleft- known as a transporter
Name 3 drugs that bind to DAT + what does this result in?
= Binding site for cocaine, amphetamine and methylphenidate
FUNCTION = Block the transporter (= DAT) that would usually take up excess dopamine = inhibits reuptake so increase dopamine in the synaptic cleft = activates post-synaptic receptors = increased signalling
What is the main deactivation method used by DAT?
uses ion gradient created by the Na+/K+ ATPase- by coupling influx of sodium ions (= symporting ion) into cytosol, it also imports dopamine i.e. energy gradient created to move dopamine back into pre-synaptic neuron
What is the function of VMAT?
= packages vesicles with dopamine- transport dopamine from cytosol into vesicles
Describe the 2 differences between VMAT and DAT
- VMAT has similar structure to DAT but small difference which determines if it is found in pre synaptic membrane (DAT) or the vesicular membrane (VMAT)
- VMAT does not use Na+ as a symporting ion- instead uses hydrogen ions in presynaptic vesicles, they are pushed down their concentration gradients at same time dopamine is moved into synaptic vesicles
What does reserpine do?
blocks VMAT-2 and depletes DA as it is not reintroduced into vesicles = Depletes all dopamine = results in Parkinsons
What happens when the DAT gene is knocked out in animals?
elevates the synaptic level of DA in all brain regions with DA terminals – enhancing DA neurotransmission in the striatum results in these rats being hyperactive
What is 6-hydroxydopamine?
(like dopamine but has + OH) – neurotoxin that is only taken up by DAT
What does 6-OHDA do?
Inhibits mitochondrial respiratory chain leads to neuronal death
= causes oxidative stress = damages neurons:
- Auto-oxidation produces hydrogen peroxide
- = Causes oxidative stress to mitochondria releasing cytochrome c leading to death of dopamine and noradrenaline neurons
What happens when 6-OHDA is injected into striatum of mice ?
- Induces oxidative stress in dopaminergic neurons
- = reduction in dopamine signalling
- = neurodegeneration by behavioural changes- Parkinsons
Name the 2 enzymes that are responsible for the metabolism of dopamine
Monoamine oxidase (MAO)
COMT
Where is MAO found?
On inner mitochondrial membrane in cells- e.g. neurons
Where is COMT found?
Cytosol but also membrane bound
Describe the role of COMT and MAO
- Each produce an intermediate
COMT produces 3-MT
MAO produces DOPAC - Enzymes act in either order to produce common metabolite HVA = inactive molecule that is secreted out of the body
What is the difference between dopaminergic, noradrenergic and adrenergic neurons?
- Dopaminergic neurons = has tyrosine hydroxylade & DOPA decarboxylase
- Noradrenergic neurons = also have dopamine b-hydroxylase
- Adrenergic neurons (e.g. chromaffin cells in the adrenal medulla) = have PNMT on top of this
Name the 5 subtypes of dopamine receptors and what do they all have in common?
= G-protein coupled receptors:
D1
D2
D3
D4
D5
Name the D1 like dopamine receptors
D1 and D5
Name the D2 like dopamine receptors
D2
D3
D4
On which neuron is each dopamine receptor found?
- D1 = Post-synaptic
- D5 = Post-synaptic
- D2= Pre- and Post-synaptic: Striatum high levels
- D3 = Post-synaptic: Nucleus accumbens - VTA pathway Presynaptic in cortex?
- D4 - Pre- and Post-synaptic: Frontal cortex, amygdala, hippocampus
What is the main difference between D1 like receptors and D2 like receptors?
D1 = positively coupled to AC/cAMP signalling
D2 = negatively coupled to AC/cAMP signalling
Compare the structure of D1 like receptors and D2 like receptors
D1 has long c terminal- D2 has short c terminal
In D2 there is a very large loop compared to D1
Describe some different cellular downstream reponses in D1 and D2 receptors
D1 = more PIP hydrolysis, calcium is increased and PKC activation = excitability increased following activation of D1
D2 = increased potassium which hyperpolarises membrane, reduces calcium = excitability reduced following activation of D2
How were dopamine neuronal pathways 1st established?
Falck – Hillarp Fluorescence 1960’s- wanted to look at brains were not necessarily looking for dopamine- to do this:
1. Freeze dried brain tissue to remove all water
2. Then exposed to formaldehyde vapor to dry it
But they observed that after exposure to formaldehyde = converted Dopamine to a fluorescent isoquinoline molecule that could be seen as a yellow green colour under the microscope
What method was used to improve Falck-Hillarp fluoresence
1980s- tyrosine hydroxylase immunohistochemistry produced even better resolution of visualizing dopaminergic neurons e.g. generate antibody against tyrosine hydroxylase = can specifically stain neurons
Name the 4 different dopamine pathways
Nigrostriatal
Mesolimbic
Mesocortical
Tuberoinfundibular
What % of neurons are dopaminergic?
1%
Where do neurons originate and stretch to in the nigrostriatal pathway?
neurons originates in substantia nigra and stretches to striatum
Where do neurons originate and stretch to in the mesolimbic pathway?
neurons originates in tegmentum / VTA and stretches to nucleus accumbens
Where do neurons originate and stretch to in the mesocortical pathway?
neurons originate in tegmentum / VTA and stretches to frontal cortex
Where do neurons originate and stretch to in the tuberinfundibular pathway?
small pathway- relates to hypothalamus
-arcuate nucleus of the hypothalamus innervate the median eminence in the anterior pituitary gland.
What does the nigrostriatal pathway control for and what does degeneration of the neurons result in?
controls planning and execution of voluntary skeletal muscle movement.
- = Degeneration of these neurones occurs in Parkinson’s disease leading to motor impairment symptoms
What does the mesolimbic pathway control for and what does overactivity of the neurons result in?
part of the limbic system controlling emotion, pleasure reward and goal-directed behaviour
- Over-activity in this pathway contributes to psychosis, delusions and hallucinations the positive symptoms of schizophrenia
What does the mesocortical pathway control for and what does underactivity of the neurons result in?
neuronal activity is associated with emotion and motivation.
- Under-activity in this pathway may contribute to negative symptoms (social withdrawal/cognitive dysfunction) seen in schizophrenia.
- Cognitive side-effects sometimes known as ‘neuroleptic-induced deficit syndrome’ may also be mediated by this pathway.
What does the tuberoinfundibular pathway control for?
Neuroendocrine associated pathway:
- DA release inhibits prolactin secretion; involved in maternal behaviour (neuroendocrine function).
