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Biochemistry III > W4 Noradrenergic Neurotransmission (Ben) > Flashcards

W4 Noradrenergic Neurotransmission (Ben) Flashcards

1
Q

What is the general structure of a catecholamine?

A

A benzene diol (2 OH grps) with an amine-containing side chain

(img = benzene diol)

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2
Q

From which AA are catecholamines synthesized?

A

Tyrosine

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3
Q

What is the first step in the synthesis of catecholamines?

Substrate?

Enzyme (and its action)?

Product?

A

Hydroxylation of benzene ring…

Substrate: Tyrosine + O2

Enzyme: Tyrosine Hydroxylase

Product: DOPA + H20

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4
Q

What is the cofactor for tyrosine hydroxylase?

And what does it become after the reaction?

A

Tetrahydrobiopterin

  • becomes dihydrobiopterin
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5
Q

What is the inhibitor for the first enzyme in the synthesis of catecholamines?

What kind of inhibition is it?

What can it be used to treat?

A

α-methyl-p-tyrosine inhibits tyrosine hydroxylase

  • competitive inhibition
  • used to treat inoperable pheochromocytoma, an NE-producing tumor of the adrenal medulla
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6
Q

What is the 2nd step in catecholamine 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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7
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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8
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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9
Q

What is the 3rd step in catecholamine synthesis, after decarboxylation?

Substrate?

Enzyme?

Products?

A

Hydroxylation of dopamine’s amine side chain (B position)…

Reactants: Dopamine + O2

Enzyme: Dopamine β-Hydroxylase

Products: Noradrenaline + H2O

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10
Q

What is the co-factor for the B-hydroxylation of dopamine?

A

Ascorbic Acid

  • becomes dehydroascorbate

(via Dopamine B-hydroxylase)

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11
Q

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

Reactants?

Enzymes?

Products?

A

Methylation of the amine group…

Reactants: Noradrenaline

Enzyme: Phenyl-ethanolamine N-methyl Transferase

Products: Adrenaline

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12
Q

What is the cofactor for the enzyme which produces adrenaline?

A

S-Adenosyl Methionine

  • methylates noradrenaline and becomes S-Adenosyl Homocysteine
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13
Q

What is the rate-limiting step in catecholamine synthesis?

A

The first step catalyzed by Tyrosine Hydroxylase…

hydroxylation of the benzene ring of Tyr

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14
Q

Phenyl-ethanolamine N-methyl transferase is present only in which cells?

A

A cells of the adrenal medulla

and small groups of neurons in the brain stem

(only these cells produce adrenaline)

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15
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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16
Q

How does phosphorylation effect tyrosine hydroxylase?

A

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

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17
Q

How does sympathetic activity affect noradrenaline synthesis?

In the short term?

And long term?

Include enzymes affected + mechanisms.

A

Short term: It increases tyrosine hydroxylase activity (despite the usual negative feed-back inhibition of the enzyme via noradrenaline).

Ca++ enters the nerve terminals via VDCCs in sympathetic activity, thus activating the enzyme.

Long term: Prolonged sympathetic activity leads to upregulation of de novo synthesis of Tyr hydroxylase and Dopamine B-hydroxylase.

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18
Q

How do steroid hormones affect the synthesis of catecholamines?

A

by increasing activity of the N-methyl Transferase…

they increase the synthesis of adrenaline

(according to the physio lecture, it is specifically cortisol which does this, when it reaches the adrenal medulla in high concentration as the microcirculation of the zona fasciculata flows towards the medulla)

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19
Q

What altered catecholamine substrate can be used to treat a cardiovascular disorder?

What disorder + how?

A

α-methyl DOPA

  • results in production of α-methyl noradrenaline which has about 1/10 the vasopressor effect normal NA, so is an effective treatment for hypertension
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20
Q

Describe the uptake of catecholamines into synaptic vesicles.

2 important components

A

It is a secondary active transport, driven by an H+-ATPase pump.

The pump creates a proton gradient which drives VMTA2, a non-specific transporter of biogenic amines.

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21
Q

What is the transporter responsible for neurotransmitter uptake into vesicles?

What is its substrate specificity?

A

VMTA2 - Vesicular Membrane Transporter 2

  • 12 TM domain transporter with broad substrate specificity for biogenic amines
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22
Q

What drug disrupts the uptake of catecholamines into synaptic vesicles?

How?

What can it treat?

A

Reserpine

  • irreversibly inhibits uptake via inhibition of VMTA2 + thus depletion of synaptic vesicles (b/c constant leakage is not balanced by uptake)
  • can be used to treat hypertension
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23
Q

What psychiatric disorder is associated with disrupted VMTA2 activity?

How is it treated?

A

Bipolar Disorder

  • treated with lithium

(check notes for the mechanism)

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24
Q

What two enzymes are involved in metabolism of noradrenaline?

A
  1. Monoamine Oxidase
  2. COMT - Catechol O-methyl Transferase
25
Q

Where is monoamine oxidase located within a cell?

A

On the outer membrane of the mitochondria.

(Although some MAO B can be found in the synapse, according to the lecture.)

26
Q

What are the two isoenzymes of MAO and how do their substrate specificities differ?

A
  1. MAO A - specific for noradrenaline + serotonin
  2. MAO B - specific for dopamine + synthetic substrates
27
Q

What is an inhibitor for MAO A?

A

Clorgilin

(check notes for anything signif about this to add)

28
Q

Name two MAO B inhibitors.

One is a treatment for a neurological disorder.

Which one, what disorder and how?

A
  1. Selegylin
  2. Deprenyl
    • used for Parkinson’s disease
    • decreases dopamine breakdown via MAO B, thus increasing DA levels
29
Q

Name an important action of extra-neuronal MAO.

What happens to this action due to MAO inhibitors and what is the effect?

A

Gastrointestinal + hepatic MAO breaks down ingested biogenic amines (tyramine, phenylethylamine), preventing them from entering the circulation.

MAO inhibition can allow these amines into the circulation, resulting in hypertension, etc.

30
Q

What co-factor does COMT require?

A

SAMe

  • methylates the product of MAO + reductase enzyme using methyl from SAMe (resulting in SAHcy)
31
Q

What important metabolite of CNS noradrenaline can be measured in bodily fluids?

Which fluids?

A

MHPG

(3-Methoxy-4-Hydroxy-phenylglycol)

  • found in urine and CSF
  • indicative of CNS NA activity

( picture below is wrong… its 4-hydroxy, not 1 )

32
Q

What metabolite of PNS noradrenaline can be found in urine?

What can elevated levels be indicative of?

A

VMA (Vanillylmandelic Acid)

  • high levels can indicate pheochromocytoma
33
Q

How are catecholamines re-uptaken into presynaptic neurons?

A

Secondary active transport via an Na-Catecholamine Symporter

34
Q

What happens to presynaptic catecholamine re-uptake in the case of sustained depolarization of the presynaptic neuron?

A

High levels of Na+ at the synaptic terminal reverse the direction of the Na-Catecholamine symporter.

(Because it relies on the sodium gradient set up by the Na-K-ATPase for normal re-uptake function + the gradient is reversed in depolarization.)

35
Q

Describe the structure of the Na-Catecholamine Symporter.

Its specificity?

Its efficiency?

A

It is a 12 TM domain protein.

It is specific for individual catecholamines (NA, DA), but diff. transporters have structural similarity.

It does not capture all the synaptic catecholamine. Some diffuses away.

36
Q

What are 2 inhibitors of the Na-Catecholamine Symporter?

A

Cocaine

Tricyclic Antidepressants

37
Q

Where are all but one of the enzymes of catecholamine synthesis found in the cell?

Which one is not found there and where is it found?

A

Most enzymes are in the cytosol…

…but dopamine B-hydroxylase is found in synaptic vesicles.

38
Q

What (sort of strange) thing happens to noradrenaline + dopamine in synaptic vesicles?

(HINT: In the case of NA in adrenal medulla cells, it allows the synthesis of adrenaline to take place once the NA has been made by dopamine B-hydroxylase.)

A

NA + DA constantly leak from synaptic vesicles into the cytosol and are returned to them by VMAT2.

In adrenal medulla cells, this allows the cytosolic methyl transferase enzyme to convert NA –> A.

39
Q

How can the G proteins coupled to the alpha-1 through beta-3 noradrenergic receptors be remembered?

A

QISSS

40
Q

Compare the NA/A affinities of the B1 and B2 adrenergic receptors.

A

B1 - approx. equal affinity for both + tends to be in organs with sympathetic innervation, so NA dominates

B2 - higher affinity for A than NA, tends to be in places with less/no sympathetic innervation

41
Q

What 2 places are B1 receptors found?

And what are their effects?

(of course there are more, but which 2 from lecture)

A

Heart muscle - positive inotropic + chronotropic effect

GI smooth muscle - relaxation

42
Q

What 3 places are B2 receptors found?

And their effects?

(again… more than 3 exist, but which 3 from lecture)

A
  1. Uterine muscle - relaxation
  2. Skeletal muscle - glycogenolysis, vasodilation
  3. Bronchi smooth muscle - dilatation
43
Q

Where are B3 receptors found mainly?

Their effect?

A

Adipose Tissue

  • activate lipolysis
44
Q

Describe the cascade of effects which results in the immediate action of B1 receptors on heart muscle.

A
  1. ​B1 –> Gs –> adenylyl cyclase –> increased [cAMP] –> PKA active
  2. PKA phosphorylates + activates LVDCC (AKA DHP receptor) allowing calcium influx
  3. Increased [Ca++]ic leads to Ca-induced Ca Release thru the RYR2** (heart isoform) on the sarcoplasmic reticulum
  4. Further increased [Ca++]ic increases contraction force
45
Q

How do the DHP-RYR1/RYR2 mechanisms differ?

A

RYR1 - in skeletal muscle, DHP activation simply induces a conformational change in RYR1 leading to Ca++ release from SR

RYR2 - in heart, DHP activation leads to Ca++ influx into cell, which leads to calcium-induced calcium release via RYR2 from the SR

46
Q

What is the “late action” of the B1 receptor in heart muscle?

Describe the cascade that produces this effect.

A

The late action is a positive chrontropic (^ HR) effect.

  1. PKA phosphorylates/deactivates phospholamban
  2. Phosphorylate phospholamban can no longer inhibit SERCA
  3. SERCA pumps Ca into SR to increase the rate of relaxation of heart muscle
47
Q

What two heart conditions can B1-selective antagonists treat due to their blocking of chrono/inotropic effects?

A

Arrhythmia

Angina

48
Q

make some cards about alpha and beta receptors on adipose tissue

skipping them for now bc her slides are confusing… talking abt glycogenolysis in adipose tissue, which is VERY minimal if it happens at all

A

ok

49
Q

How is glycogen metabolism regulated by cholinergic (nAChR) stimulation of skeletal muscle?

A

Neural stimulation of muscle contraction via nAChRs leads to increased intracellular calcium.

This calcium binds to the delta subunit (very similar to calmodulin) of phosphorylase kinase, partially activating it.

(It is fully activated when A/B subunits are P-ated by PKA)

50
Q

How does adrenergic stimulation of skeletal muscle result in glycogen metabolism regulation?

A
  1. B2 receptors –> –> –> PKA activation
  2. PKA phosphorylates α/β subunits of phosphorylase kinase, fully activating it
  3. PKA also P-ates glycogen synthase kinase, which then P-ates + inactivates glycogen synthase
51
Q

How does adrenergic stimulation via B receptors (not A!) affect smooth muscle?

Give the detailed mechanism, not just the effect.

A

B receptor stimulation relaxes smooth muscle…

  1. Gs –> –> –> PKA
  2. PKA phosphorylates myosin light chain kinase, which inactivates it
52
Q

What are the 2 relevant effects of α1 receptor stimulation?

(According to the slides.)

A
  1. Increased glycogenolysis
  2. Vascular SM contraction
53
Q

What are the 3 relevant effects of α2 receptor stimulation?

(According to the slides.)

A
  1. GI SM relaxation
  2. inhibition of lipolysis
  3. platelet aggregation
54
Q

What are the 2 relevant effects of β1 receptor stimulation?

(According to the slides.)

A
  1. Stimulation of lipolysis
  2. Increased HR + contractility
55
Q

What are the 3 relevant effects of β2 receptor stimulation?

(According to the slides.)

A
  1. Increased glycogenolysis
  2. Increased gluconeogenesis
  3. SM relaxation
    • bronchi
    • vessels
    • GI SM
56
Q

How does adrenergic stimulation affect glycogen metabolism in the liver?

Give receptor, mechanism + final effect.

A

α-1 receptors lead to…

  • Calcium increase –> Ca-Calmodulin complex
  • Activation of phosphorylase kinase (via CAM-dep. kinase?)
  • P-ation + activation of glycogen phosphorylase
  • Increased glycogenolysis
57
Q

How does adrenergic stimulation have a two-fold effect on GI smooth muscle?

A
  1. Direct stimulation via B1 receptor –> relaxation
  2. Indirect effect via A2 receptor on cholinergic axon terminals inhibits ACh release to mAChRs –> further relaxation

(not entirely sure thats what this picture means since she hasn’t gone over it yet in lecture, but it’s the best i could figure from Wiki)

58
Q

make a card abt this img…

dont understand/remember how Ca-CAM can activate MLCK and lead to vasoconstriction

A

OK

Biochemistry III (35 decks)

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