WK5 Serotonergic Transmission (Ben)

Question 1

The serotonergic system consists of _________ axons from the cell bodies in the __________.

(Super general statement from the slides…)

Answer 1

The serotonergic system consists of ascending axons from the cell bodies in the raphe nuclei.

Question 2

What is the 1st step in the synthesis of serotonin?

Answer 2

Tryptophan Hydroxylase hydroxylates the benzen ring of tryptophan’s indole side chain to produce…

5-HTP (5-hydroxyl tryptophan)

Question 3

What is the co-factor for tryptophan hydroxylase?

Answer 3

Just as with tyrosine hydroxylase…

tetrahydrobiopterin

(–> dihydrobiopterin after reaction)

Question 4

What is the 2nd step in serotonin synthesis?

Answer 4

AAA decarboxylase removes the carboxyl group of 5-HTP to make…

serotonin (5-hydroxy tryptamine, 5-HT)

Question 5

What is the co-factor for AAA decarboxylase?

Answer 5

PLP

Question 6

What other amino acids use identical transporters to the Trp transporter to get into the brain?

Answer 6

Phe, Leu, Met

(this is all the slide said on this… not sure if it means they actually all use the same transporter… maybe leading to competition… or if they each have their own, but there is homology btwn them)

Question 7

In what kind of cells is Trp hydroxylase found?

Answer 7

only in serotonergic neurons

(this is according to the slide, BUT there are 2 isoforms… TPH 1 is in peripheral serotonogenic tissues such as the GI tract, whereas TPH2 is the neural-only form)

Question 8

What is the Km for Trp hydroxylase?

And what does this mean for its function in the brain?

(the number is probably not that important, but learn it anyway!)

Answer 8

30-60 micromolar

• at normal physiological Trp concentrations in the brain, the enzyme is not saturated, so eating more tryptophan can -> increased synthesis of serotonin

Question 9

How is Trp hydroxylase regulated on a short-term basis?

Answer 9

Via stimulatory phosphorylation

• PKA and CAMK2 (calmodulin-dependent) can phosphorylate its regulatory domain’s Ser residues and increase its activty

Question 10

this is a placeholder for a card about long term upregulation of Trp OHase

dont get what the slide says about it… not very detailed

Answer 10

OK

Question 11

What is the 1st step in melatonin synthesis (starting from serotonin) ?

Answer 11

5-HT N-Acetyltransferase adds an acetyl group onto serotonin’s amine group, producing…

N-acetyl serotonin

(AKA Serotonin N-Acetyltransferase or SNAT)

Question 12

What is the 2nd (and final) step of melatonin synthesis?

Answer 12

Methylation of indole hydroxyl group of N-acetyl serotonin via the enzyme 5-hydroxyindole O-methyltransferase, producing…

melatonin.

Question 13

What is the co-factor of 5-HT N-acetyltransferase?

(not in the slides but simple if you think about its function)

Answer 13

It needs acetyl-CoA to perform its acetylation reaction.

The rxn results in an acetylated product and release of CoA-SH.

Question 14

What is the cofactor of the last enzyme in the synthesis of melatonin?

(also not in the slides, but simple if you think about it)

Answer 14

The enzyme is 5-hydroxyindole O-methyltransferase, so…

the cofactor is SAMe (S-adenosyl methionine).

(S-adenosyl homocysteine is produced.)

Question 15

What is the regulatory step of melatonin synthesis?

How is it regulated?

Answer 15

The 5-HT N-acetyltransferase step is regulated by…

1. Decreased light to the retina…
2. Relay via suprachiasmatic nucleus…
3. Increased NE stimulation of beta adrenergic-receptors in pineal…
4. cAMP increase –> PKA –>
5. phosphorylation and activation of the enzyme

Question 16

What kind of receptors in which part of the CNS play a role in regulating diurnal rhythm?

Answer 16

muscarininc M_1a and M_1b receptors in the pituitary and suprachiasmatic nucleus

Question 17

How is serotonin taken up in vesicles?

Answer 17

also by the VMAT (vesicular monoamine tranpsorter) which exchanges a proton for the serotonin

Question 18

What can inhibit BOTH pre-synaptic and vesicular uptake of serotonin?

Answer 18

Amphetamine derivatives:

fenfluramine

ecstasy (MDMA)

Question 19

How is serotonin re-uptaken into pre-synaptic neurons?

Answer 19

Via the SERT, serotonin/Na symporter.

• 50% homologous to the DA and NA sodium symporters

Question 20

What 3 things can inhibit SERT?

Answer 20

1. SSRIs
2. tricyclic antidepressants
3. cocaine

Question 21

How is serotonin metabolized?

To what metabolite, which can also be measured in urine?

Answer 21

MAO A (A isoform more specif. for 5-HT)

and

Aldehyde Dehydrogenase

make

5-hydroxyindoleacetic acid

Question 22

Other than MAOIs, TCAs and SSRIs…

what kind of serotonergic anti-depressant/anxiety medications are there?

Answer 22

“Novel anxiolytic” medications which act as 5-HT1A receptor agonists.

Question 23

What is the mechanism of serotonergic anti-schizophrenia medications?

Answer 23

The “atypical antipsychotics” act as inhibitors of the 5-HT2 receptors.

(These drugs also affect DA receptors. The “typical” antipsychotics are specifically dopamine receptor antagonists.)

Question 24

What serotonergic medications can be used to treat nausea?

Answer 24

5-HT3 Receptor Antagonists

• such as Ondansetron

Question 25

What is the mechanism by which chemotherapy causes nausea?

Answer 25

Chemotherapy triggers…

1. 5-HT release from enterochromaffin cells of the GI tract
2. 5-HT stimulates visceral afferent neurons via their 5-HT3Rs
3. Depolarization of these neurons leads to…
4. Chemoreceptor activation, which induces…
5. Nausea! (Hooray).

Question 26

What drug can be used to treat migraines thought to be resulting from decreased serotonergic activity?

How does it work?

Answer 26

Sumatriptan

• is a 5-HT1B, D and F agonist
• acts on these receptors found in cranial and basilar arteries to induce their vasoconstriction

(they tend to be inflamed and dilated in migraine patients)