WK5 Dopaminergic Transmission (Ben) Flashcards
What two general neurally-controlled processes does dopaminergic neurotransmission contribute to?
Reward and movement regulation.
Describe the direct nigro-striatal pathway.
(This information is half from neuroanatomy, probably more detail than we need for biochem, but whatever.)
- Dopaminergic neurons in Substantia nigra –>
- D1 receptor stimulates the putamen –>
- inhibition of the globus pallidus internus –>
- inhibition of the thalamus (VA/VL)
- thalamus stimulates the cerebral cortex
Outcome: 2 inhibitions = stimulation
Describe the indirect nigro-striatal pathway.
(This information is half from neuroanatomy, probably more detail than we need for biochem, but whatever.)
- Dopaminergic neurons in Substantia nigra –>
- D2 receptor inhibits the putamen –>
- inhibition of the globus pallidus externus –>
- inhibition of the subthalamic nucleus –>
- stimulation of the globus pallidus internus –>
- inhibition of the thalamus (VA/VL)
- thalamus stimulates the cerebral cortex
Outcome: 4 inhibitions = stimulation
What enzyme is missing in dopaminergic neurons that keeps them from continuing down the catecholamine synthesis pathway to make NE + E?
Where would this enzyme normally be found within a cell?
Dopamine B-Hydroxylase
- normally found within the synaptic vesicles of noradrenergic neurons + adrenal medulla cells
What is the first step in the synthesis of dopamine?
Substrate?
Enzyme (and its action)?
Product?
Hydroxylation of benzene ring…
Substrate: Tyrosine + O2
Enzyme: Tyrosine Hydroxylase
Product: DOPA + H20
What is the cofactor for tyrosine hydroxylase?
And what does it become after the reaction?
Tetrahydrobiopterin
- becomes dihydrobiopterin
What is the 2nd step in dopamine synthesis, after hydroxylation?
Reactants?
Enzyme?
Products?
Decarboxylation of the tyrosine-derived carboxyl group…
Reactants: DOPA
Enzyme: Aromatic AA Decarboxylase
Products: Dopamine + CO2
What is the cofactor for the 2nd enzyme in catecholamine synthesis?
Pyridoxal Phosphate (PLP)
- active form of vitamin B6
What is the rate-limiting step in dopamine synthesis?
The first step catalyzed by Tyrosine Hydroxylase…
hydroxylation of the benzene ring of Tyr
In what tissues is aromatic AA decarboxylase found?
In catecholaminergic AND serotonergic neurons, as well as blood vessel + kidney tissues
Name 3 mechanisms for regulation of the enzyme which produces DOPA.
Tyrosine hydroxylase is regulated by:
- Noradrenaline - negative feed-back inhibition
- Ca++ - activates the enzyme
- Kinases - PKA/PKC/Ca-Calmod.-dep. Kinase all phosphorylate + stimulate the enzyme
How does phosphorylation affect tyrosine hydroxylase?
It stimulates it by increasing affinity for its tetrahydrobiopterin co-factor.
How is dopamine taken up into synaptic vesicles?
What inhibits this?
VMTA 2 - vesicular membrane transport protein
- exchanges NTs for hydrogen ions
- inhibited irreversibly by reserpine (high affinity)
(annoyingly, the slides say VMTA2 but I’m pretty sure its VMAT2 = vesicular monoamine transporter … the only thing anything like VMTA found on Wikipedia)
List the dopamine receptors and their signalling mechanisms.
- D1 - Gs
- D2 - Gi
- D3 - unknown
- D4 - unknon
- D5 - Gs
- the intracellular targets of Gs-stimulated phosphorylation via PKA in dopaminergic neurons are also not clear
How is dopamine taken back up into the pre-synaptic neuron?
Describe the transporter (4 characteristics).
Same as with noradrenaline…
via an Na+/Catecholamine Symporter
- 12 TM segments
- Secondary active transport
- Sustained depolarization reverses function ( due to increased [Na+]IC )
- Specific to different catecholamines, but large homology btwn types
What inhibits the re-uptake of dopamine into pre-synaptic neurons?
2 things
- Cocaine
- Tricyclic Antidepressants
(both via inhibition of the Na/Catecholamine Symporter)
What dopamine metabolite can be found in urine to indicate the functional state of dopaminergic neurons?
What two disorders can result in a shift in normal levels of this metabolite?
And which way does it shift for each?
Homovanillic Acid
- levels go up in schizophrenia
- levels go down in Parkinson’s disease
What is the 1st step in dopamine metabolism? (not synthesis)
MAO converts dopamine to…
DOPAC (3,4-dihydroxy phenylacetaldehyde)
(by removing NH3 + adding an =O)
What is the 2nd step in dopamine metabolism? (not synthesis)
HINT: results in an unnamed intermediate, not the final product found in the urine
(at least it was unnamed on the lecture slides)
Aldehyde dehydrogenase converts DOPAC (3,4-dihydroxy-phenylacetaldehyde) to…
an unnamed carboxylic acid intermediate
(probably not that important of a step, exam-wise)
What is the last step in the metabolism (not synthesis) of dopamine?
HINT: resulting in the metabolite found in the urine
COMT (catechol O-methyl transferase) methylates the carboxylic acid intermediate on one of its phenyl hydroxyl groups to form…
homovanillic acid
What is the difference between the two MAO isoforms in terms of substrate specificity?
MAO A - metabolizes NE, 5-HT, DA and tyramine
whereas
MAO B - mostly metabolizes DA
What are 3 options for Parkinson’s treatment?
- L-DOPA - add exogenous dopamine synthesis intermediate
- Deprenyl/Selegeline - selective MAO B inhibitor (metabolism inhibition without “cheese effect” of MAO A inhibition)
- Dopamine Receptor Agonists - can be helpful, but may induce schizophrenic symptoms
What is an issue encountered with L-DOPA treatment and how is it overcome?
Peripheral AAA Decarboxylase breaks down most of the administered L-DOPA before it reaches the brain…
Peripheral AAA Decarboxylase inhibitor Carbidopa can be administered to decreases this effect + allow more L-DOPA to enter the brain.
(Carbidopa does not enter the brain itself, so there is no inhibition of CNS dopamine synthesis)
What are two general mechanisms thought to be involved in schizophrenia?
- Increased dopaminergic activity
- Decreased glutamatergic activity
What element of the dopaminergic system is often expressed in greater amounts in people with schizophrenia?
Increased number of D2 receptors
(Because there’s more dopamine in the brain, you see more homovanillic acid in the CSF)
