Adrenergic receptors and synapses Flashcards
What molecules synthesise acetylcholine?
Choline + Acetyl coenzyme A
Catalysed by choline acetyltransferase
What molecules synthesise Noradrenaline?
Tyrosine + Tyrosine hydroxylase (limiting reagent) —> DOPA
DOPA + DOPA decarboxylase —> Dopamine
Dopamine + Dopamine beta-hydroxylase —> Noradrenaline
How does choline and tyrosine enter the synapses?
Na+ transporter (symporter)
What receptors does noradrenaline act on?
Adrenergic
What receptors does acetylcholine act on?
Muscarinic
Nicotinic
What type of receptors are nicotinic?
Ligand gated ion channels
What type of receptors are muscarinic?
GPCR
Where are adrenergic receptors found?
At the end of the post-ganglionic neuron for the sympathetic nervous system
Where are nicotinic receptors found?
At the ganglionic synapse for both the parasympathetic and sympathetic NS
Where are muscarinic receptors found?
At the end of the post-ganglionic neuron for the parasympathetic NS
Summarise how vMAT works and what its function is
Function = transporting NA into vesicles for transportation
Hydrolysis of ATP = H+ into vesicle
Proton pump = H+ out, NA in
What inhibits vMAT?
Reserpine
What is the consequence of reserpine?
NA not transported and released
Doesn’t act on adrenergic receptors
Sympathetic affects cant be produced
Decrease HR
Decrease in renin release
What causes Ca2+ to be released
Action potential - depolarisation = Ca2+ channels open
What type of channels are Ca2+
L-type voltage gated ion channels
Where does Ca2+ get released into?
Pre-synaptic terminal
What is the consequence of an increase in Ca2+?
Vesicle fusion to membrane and release of neurotransmitter
What is the process called for the release of the neurotransmitter?
Exocytosis
What drug blocks the release of the neurotransmitter?
Guanethidine
What is the enzyme responsible for breaking down acetylcholine in the synaptic clef?
Acetylcholinesterase
Why is noradrenaline metabolism important?
Terminates noradrenaline
What are the 2 enzymes responsible for metabolising NA?
MAO - monoamine oxidase
COMT - Catechol-O-methyl transferase
What does MAO metabolise NA to?
An aldehyde
What does COMT metabolise NA to?
Carboxylic acid
What cofactor does COMT use?
SAM - S Adenosyl methionine
What type of enzyme is COMT?
Mg2+ metalloprotease
Why are using MAO or COMT inhibitors not beneficial?
Because noradrenaline has a high percentage of reuptake meaning it can be recycled and the process can happen again
What do selective seretonin reuptake inhibitors inhibit?
Inhibit reuptake of 5-HT
How do neurotransmitters pass the synaptic clef?
Diffusion
What type of receptors are adrenergic receptors?
GPCR
What are the 3 adrenergic binding sites and what amino acids do each of them have?
TM3 - aspartic residue
TM5 - X2 Serine residue
TM6 - Phenylaniline and asparagine
What enantiomer must the alcohol group be on a drug for beta 2 agonists?
R- enhances activity
What type of amines must the drug have for optimal activity?
Secondary
What gives beta selectivity over alpha?
Substituted hydrophobic chain from amine
What is the downstream effects of beta2 agonists?
G alpha s
Increase cAMP + PKA
PKA deactivates MLCK
MLCK can phosphorylate myosin
no smooth muscle contraction
Why is a substitution on the meta carbon important for beta2 agonists?
Stops the metabolism of the drug by COMT - wont become inactivated
What must the meta substituent be able to do on beta 2 agonists?
Hydrogen bond
What are the differences between beta 2 agonists and beta1 antagonists?
1) perpendicular ring
2) Alcohol group in S enantiomer
3) Short hydrophobic interactions
What increases the activity of beta 2 agonists?
long hydrophobic chain separated by an ether
Summarise the development of beta blockers
1) Alpha vs Beta selectivity - hydrophobic chain on amine
2) Agonist vs antagonist - linking group
3) Beta 1 vs beta 2 - hydrogen bonding group in para position
