Adrenergic transmission

Question 1

How does the nervous system result in the release of adrenaline?

Answer 1

preganglionic neurone in symapthetic neurones secrete ACh which then stimulates the post ganglionic neurone which secretes noradrenaline

ACh also binds to adrenal medulla which stimulates the release of adrenaline into the circulatory system

Question 2

catecholamine definition

Answer 2

a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side chain amine

water soluble, 50% bound to plasma proteins in circulation

Question 3

What are catecholamines derived from?

Answer 3

tyrosine amino acids, from dietary sources as well as synthesis from phenylalanine

Question 4

Examples of catecholamines

Answer 4

include epinephrine, norepinephrine and dopamine

Question 5

where are catecholamine synthesised?

Answer 5

chromaffin cells of the adrenal medulla of the adrenal gland and a small number of neurons in the medulla oblongata

Question 6

stages of biosynthesis

Answer 6

tyrosine is actively moved into nerve varicosity via sodium dependent aromatic L-amino acid transporters

1. tyrosine first oxidised to L-DOPA by tyrosine hydroxylase
2. L-DOPA is decarboxylated to give dopamine
3. dopamine is then converted to noradrenaline by dopamine beta-hydroxylase
4. primary amine of noradrenaline is methylated to form adrenaline. Reaction catalysed by phenylethanolamine N- methyltransferase

Question 7

Which is the rate limiting enzyme?

Answer 7

tyrosine hydroxylase

Question 8

Key features of tyrosine hydroxylase

Answer 8

loosely associated with endoplasmic reticulum

iron and tetrahydrobiopterdine are cofactors

enzyme is subject to feedback inhibition by noradrenaline. Competes for biopterin binding site

actively regulated by phosphorylation

Question 9

agents that inhibit each enzyme

Answer 9

tyrosine hydroxylase- methyltyrosine - competitive inhibitor of THase, reducing the amount of enzyme

dopa decarboxylase- Carbidopa- peripheral inhibitor, reduces peripheral side effects and effective dose in L-DOPA therapy

dopamine hydroxylase- Disulfuriam- reduces noradrenaline/adrenaline synthesis- inhibits aldehyde dehydrogenase so can be used for alcholism

Question 10

What can be used to treat Parkinson’s?

Answer 10

L DOPA- increases dopamine, noradrenaline and adrenlaine synthesis, which raises dopamine levels in brain

Question 11

False transmitters definition

Answer 11

An agent which is structurally related to the actual transmitter, however is not as effective as the endogenous transmitter

Question 12

Example of a false transmitter and stages of its transformation

Answer 12

Methyldopa

1. taken into adrenergic nerve endings and converted into methyldopamine via DOPA carboxylase
2. dopamine hydroxylase converts methyldopamine into methylnoradrenaline
3. methylnoradrenaline is then stored in the vesicles for release

methylnoradrenaline is a better transmitter than noradrenaline in alpha 2, therefore suppress the release of that transmitter

Question 13

How is noradrenaline stored in cells?

Answer 13

High noradrenaline stored in cytoplasmic vesicles

bound loose ionic forces along with ATP and chromogranin A which prevent osmotic transport

Question 14

How are catecholamines moved into the vesicles?

Answer 14

transported via VMAT-2 vesicular monoamine transporter

driven by proton gradient set up by ATP dependent proton pump

Question 15

What does Reserpine cause?

Answer 15

Binds to amine binding site to block uptake and deplete stored noradrenaline due to leak from vesicle

acts in the periphery and brain

previously used as an antihypertensive depression

recovery require synthesis of new vesicles

Question 16

What influences release of noradrenaline?

Answer 16

adrenergic neurone blocking drugs- guanethidine, bretylium

presynaptic autoreceptors

indirectly acting sympathomimetics

Question 17

Explain adrenergic neurone blocking drugs

Answer 17

drugs carried into nerve by Uptake 1

low doses- block release of NA by action potentials- mechanism may involve hyperpolarisation of nerve endings through calcium channels

high doses- indirectly acting sympathomimetic effect

Question 18

explain presynaptic autoreceptors

Answer 18

all sympathetic/adrenergic nerve end express alpha 2 adrenoreceptors

noradrenaline activates negative feedback to decrease transmitter release

other receptors

Question 19

how is noradrenaline removed?

Answer 19

Uptake 1, located on presynaptic nerve terminals recycles around 70% of released noradrenaline

uptake 2- located on postsynaptic cells uptake

metabolism of the remainder of NA and adrenaline in liver- moves via diffusion

Question 20

Uptake 1 explained

Answer 20

12 transmembrane domain NET

sodium dependent

blocked by cocaine and tricyclic antidepressants

Question 21

uptake 2 explained

Answer 21

extra neuronal transport protein ENT

not sodium dependent

also carries dopamines and other amines

blocked by corticosteroids

Question 22

How is noradrenaline metabolised?

Answer 22

monoamine oxidase (MAO) enzyme

• found in mitochondrial matrix and extracellularly within the nerve varicosities
• metabolises catecholamines
• 2 isoezymes- MAO-A and MAO-B

Catechol O-methyl transferase

• cytoplasmic enzyme found in liver, kidney and other tissues
• metabolises most catecholamines
• often associated with uptake 2

Question 23

How are different inhibitors used as treatments?

Answer 23

depression tranylcypromine- non selective

clorgiline- MAO-A inhibitor to treat depression

selegiline- MAO-B inhibitor to treat Parkinson’s

Question 24

amphetamine action

Answer 24

potent full agonist of trace amine-associated receptor 1, a Gs and Gq coupled GPCR