Physiology and Pharmacology 9: (Challis) Adrenoceptors 1

Question 1

What is adrenaline and where is it released?

What is noradrenaline and where is it released?

Answer 1

Adrenaline = Hormone, released from chromaffin cells in the adrenal medulla

Nordadrenaline = Neurotransmitter, released by noradrenergic neurons in the central and automatic nervous systems

Question 2

Which neurotransmitters and receptors are present in efferent peripheral parasympathetic nerves?
efferent peripheral sympathetic nerves?

Answer 2

Parasympathetic (rest and digest)
1st synapse -> Ach + nAChR (pre-ganglionic)
2nd synapse -> Ach + mAChR (post ganglionic)

Sympathetic (fight or flight)
1st synapse -> Ach + nAChR (pre-ganglionic)
2nd synapse -> NA + Adrenoceptors (post ganglionic)

Question 3

What are noradrenergic varicosities?

Answer 3

• Long postganglionic sympathetic fibers lead from the sympathetic chain to the target organ where they are terminated
• Terminate with bulbous enlargements called varicosities.
• This modified axon endings release a neurotransmitter (in the case of sympathetic nervous system noradrenaline) at post-ganglionic neuroeffector junction

Question 4

Describe synthesis of noradrenaline

Answer 4

Tyrosine imported into cell

Tyrosine then hydrolysed by tyrosine hydroxylase, converting it to DOPA

DOPA converted to Dopamine which is taken up by vesicles and further converted into noradrenaline

Chromaffin cells on adrenal medulla express enzyme phenylthanolamine N-methyltransferase, which converts noradrenaline to adrenaline hormone

Question 5

Key steps in adrenergic transmission?

Answer 5

Synthesis

Storage/compartmentation
- noradrenergic terminal vesicles possess a dopamine/noradrenaline transporter that allows accumulation at high concentrations

Release
- noradrenaline release is triggered by depolarisation of the nerve terminal, Ca2+ influx and vesicle fusion with pre-synaptic plasma membrane

Signal transmission
- Released noradrenaline can bind adrenoceptors located either pre or post synaptically

Signal termination
- rapidly removed by Uptake-1 (NET) or Uptake-2 mechanisms

Metabolism
- most (90%)repackaged into vesicles, rest is metabolised by MAO and COMT

Question 6

Describe 2 methods of manipulating adrenergic transmission at the level of synthesis

Answer 6

alpha-methyltyrosine
-> analogue of tyrosine which competitively inhibits tyrosine hydroxylase, blocking de novo noradrenaline synthesis

alpha-methylDOPA
-> analogue of DOPA, converted into different form of noradrenaline (alpha-methylnoradrenaline) which is more resistant to metabolism via MAO and COMT -> accumulates in vesicles over time
- also selective agonist at some AR e.g. alpha2-adrenoceptors (not all ARs)
THEREFORE results in accumulation of ‘false transmitter’ which out-competes noradrenaline and results in decreased transmission at effector junctions

Question 7

What are the roles of pre-synpatic receptors? specifically alpha2-adrenoceptors

Answer 7

Presynaptic receptors often response to transmitter released by terminal ‘autoreceptors’ -> results in increase or decrease in likelihood of further transmitter release

alpha2-adrenoceptors act as inhibitory autoreceptors -> decrease noradrenaline release

They are Gi coupled GPCRs which decrease AC activity -> decrease Ca2+ channel opening

agonists and antagonists can act on these to manipulate pathway

Question 8

Other types of drugs which regulate noradrenaline pathway?

Answer 8

NET inhibitors -> inhibit reuptake of adrenaline e.g. cocaine, tricyclic antidepressants

Indirectly-acting sympathomimetic amines: false substrates for NET -> accumulate in varicosities and cause release of NA e.g. amphetamines, ephedrine