Lecture 8 - Adrenergic Neurotransmission

catecholamines

chemical messengers (neurotransmitters and hormones) like dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), produced mainly by the adrenal glands

where does NE function

neuroeffector junction and CNS

catecholamine SAR

• Catechol: 3,4-dihydroxyphenyl; phenols and catechols are weak acids (pKa ~ 10)

• Amine: 1o or 2o amines, strongly basic (pKa ~ 9). Predominantly ionized at pH 7.4. Ionized form (+ charge) is required for binding to adrenergic receptors.

• Phenylethyl: spacer + aromatic ring

• Optical isomerism: Norepinephrine (NE) and Epinephrine (Epi) (β-OH group). The R-enantiomers are more potent than the S-enantiomers

catecholamine instability (what rxns can it go through)

oxidation to turn -OH on catechol to O=C, COMT O-methylation to turn a -OH on catechol into H3CO

biosynthesis of catecholamine location

presynaptic neurons

overall mechanism of catecholamine biosynthesis

rate limiting step of of catecholamine biosynthesis

L tyrosine —> L-DOPA via tyrosine hydroxylase and Fe2+,O2,folate

order of catecholamine formation

dopamine —> norepinephrine —> epinephrine

where is norepinephrine stored

adrenergic presynaptic nerve terminals in storage vesicles as granules

when is NE released

Released in response to an action potential, which depolarizes the neuronal cell membrane.

what lets NE get into synaptic cleft

Ca2+ entering nerve ending due to action potential

what happens when NE binds the presynaptic alpha 2 receptor (in synapse)

1. Amount of NE released is DECREASED.

2. Reuptake of NE from the synapse into presynaptic neuron is INCREASED.

3. Biosynthesis of NE is DECREASED

goal when NE binds to presynaptic neuron in synapse

lessen adrenergic neurotransmission (vacuum up what’s in synapse)

where are adrenergic receptors located

both pre- and -post synaptically

what does alpha1 – Gq do

activation of PLC (effector) which catalyzes the hydrolysis of PIP2 to produce DAG and IP3 (second messengers)

what does alpha 2 – Gi do

inhibits adenylate cyclase (effector) and decrease formation of cAMP (second messenger)

what does beta - Gs do

beta 1-cardiac, beta 2-bronchial, uterine, vascular smooth muscles, beta 3-adipose stimulate adenylate cyclase (effector) and increase cAMP (second messenger) production

how does NE interact with receptors

3 point contact interaction

where are most adrenergic receptors found

post-synaptically

stereochemistry and NE binding interactions (in terms of -OH group)

R enantiomer lets beta -OH group form H-bond with hydroxyl site, while S-enantiomer and desoxy derivative have beta -OH facing away from hydroxyl site and don’t bond as effectively

2nd messenger when alpha 1 stimulated

PIP2 —> IP3 + DAG and Ca2+ channel

2nd messenger when alpha 2 stimulated

inhibits AC presynaptically, involved in post synaptic Ca2+ channel

2nd messenger when beta 1 stimulated

stimulate AC

2nd messenger when beta 2 stimulated

stimulate AC

what does AC stand for

adenyl cyclase

major route of NE termination

reuptake by presynaptic neuron via active uptake transporter

role of MAO (monoamine oxidase)

breaks down (oxidizes) monoamine neurotransmitters like serotonin, dopamine, and norepinephrine

degradation of NE via MAO

through oxidative deamination and oxidation, gets back to COMT

degradation of NE via COMT

through O-methylation, NE becomes inactive