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Y Biochem III > WK5 Dopaminergic Transmission (Ben) > Flashcards

WK5 Dopaminergic Transmission (Ben) Flashcards

1
Q

What two general neurally-controlled processes does dopaminergic neurotransmission contribute to?

A

Reward and movement regulation.

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2
Q

Describe the direct nigro-striatal pathway.

(This information is half from neuroanatomy, probably more detail than we need for biochem, but whatever.)

A
  1. Dopaminergic neurons in Substantia nigra –>
  2. D1 receptor stimulates the putamen –>
  3. inhibition of the globus pallidus internus –>
  4. inhibition of the thalamus (VA/VL)
  5. thalamus stimulates the cerebral cortex

Outcome: 2 inhibitions = stimulation

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3
Q

Describe the indirect nigro-striatal pathway.

(This information is half from neuroanatomy, probably more detail than we need for biochem, but whatever.)

A
  1. Dopaminergic neurons in Substantia nigra –>
  2. D2 receptor inhibits the putamen –>
  3. inhibition of the globus pallidus externus –>
  4. inhibition of the subthalamic nucleus –>
  5. stimulation of the globus pallidus internus –>
  6. inhibition of the thalamus (VA/VL)
  7. thalamus stimulates the cerebral cortex

Outcome: 4 inhibitions = stimulation

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4
Q

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?

A

Dopamine B-Hydroxylase

  • normally found within the synaptic vesicles of noradrenergic neurons + adrenal medulla cells
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5
Q

What is the first step in the synthesis of dopamine?

Substrate?

Enzyme (and its action)?

Product?

A

Hydroxylation of benzene ring…

Substrate: Tyrosine + O2

Enzyme: Tyrosine Hydroxylase

Product: DOPA + H20

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6
Q

What is the cofactor for tyrosine hydroxylase?

And what does it become after the reaction?

A

Tetrahydrobiopterin

  • becomes dihydrobiopterin
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7
Q

What is the 2nd step in dopamine synthesis, after hydroxylation?

Reactants?

Enzyme?

Products?

A

Decarboxylation of the tyrosine-derived carboxyl group…

Reactants: DOPA

Enzyme: Aromatic AA Decarboxylase

Products: Dopamine + CO2

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8
Q

What is the cofactor for the 2nd enzyme in catecholamine synthesis?

A

Pyridoxal Phosphate (PLP)

  • active form of vitamin B6
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10
Q

What is the rate-limiting step in dopamine synthesis?

A

The first step catalyzed by Tyrosine Hydroxylase…

hydroxylation of the benzene ring of Tyr

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14
Q

In what tissues is aromatic AA decarboxylase found?

A

In catecholaminergic AND serotonergic neurons, as well as blood vessel + kidney tissues

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16
Q

Name 3 mechanisms for regulation of the enzyme which produces DOPA.

A

Tyrosine hydroxylase is regulated by:

  1. Noradrenaline - negative feed-back inhibition
  2. Ca++ - activates the enzyme
  3. Kinases - PKA/PKC/Ca-Calmod.-dep. Kinase all phosphorylate + stimulate the enzyme
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17
Q

How does phosphorylation affect tyrosine hydroxylase?

A

It stimulates it by increasing affinity for its tetrahydrobiopterin co-factor.

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18
Q

How is dopamine taken up into synaptic vesicles?

What inhibits this?

A

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)

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19
Q

List the dopamine receptors and their signalling mechanisms.

A
  1. D1 - Gs
  2. D2 - Gi
  3. D3 - unknown
  4. D4 - unknon
  5. D5 - Gs
  • the intracellular targets of Gs-stimulated phosphorylation via PKA in dopaminergic neurons are also not clear
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20
Q

How is dopamine taken back up into the pre-synaptic neuron?

Describe the transporter (4 characteristics).

A

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
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21
Q

What inhibits the re-uptake of dopamine into pre-synaptic neurons?

2 things

A
  1. Cocaine
  2. Tricyclic Antidepressants

(both via inhibition of the Na/Catecholamine Symporter)

22
Q

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?

A

Homovanillic Acid

  • levels go up in schizophrenia
  • levels go down in Parkinson’s disease
23
Q

What is the 1st step in dopamine metabolism? (not synthesis)

A

MAO converts dopamine to…

DOPAC (3,4-dihydroxy phenylacetaldehyde)

(by removing NH3 + adding an =O)

24
Q

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)

A

Aldehyde dehydrogenase converts DOPAC (3,4-dihydroxy-phenylacetaldehyde) to…

an unnamed carboxylic acid intermediate

(probably not that important of a step, exam-wise)

25
Q

What is the last step in the metabolism (not synthesis) of dopamine?

HINT: resulting in the metabolite found in the urine

A

COMT (catechol O-methyl transferase) methylates the carboxylic acid intermediate on one of its phenyl hydroxyl groups to form…

homovanillic acid

26
Q

What is the difference between the two MAO isoforms in terms of substrate specificity?

A

MAO A - metabolizes NE, 5-HT, DA and tyramine

whereas

MAO B - mostly metabolizes DA

27
Q

What are 3 options for Parkinson’s treatment?

A
  1. L-DOPA - add exogenous dopamine synthesis intermediate
  2. Deprenyl/Selegeline - selective MAO B inhibitor (metabolism inhibition without “cheese effect” of MAO A inhibition)
  3. Dopamine Receptor Agonists - can be helpful, but may induce schizophrenic symptoms
28
Q

What is an issue encountered with L-DOPA treatment and how is it overcome?

A

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)

29
Q

What are two general mechanisms thought to be involved in schizophrenia?

A
  1. Increased dopaminergic activity
  2. Decreased glutamatergic activity
30
Q

What element of the dopaminergic system is often expressed in greater amounts in people with schizophrenia?

A

Increased number of D2 receptors

(Because there’s more dopamine in the brain, you see more homovanillic acid in the CSF)

Y Biochem III (34 decks)

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