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UEA Peripheral Nervous System and Synaptic Pharmacology

Summer Project 2013
by

Mahmoud Abdelhamid

on 4 December 2015

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Transcript of UEA Peripheral Nervous System and Synaptic Pharmacology

UEA Peripheral Nervous System & Synaptic Pharmacology
Noradrenergic Synapse
Cholinergic Synapse
Choline Acetyltransferase (CAT) enzyme synthesises Acetylcholine from Choline & Acetyl co-enzyme A
Acetylcholine is packaged into vesicles via a
hydrogen-coupled transporter
Arrival of action potential results in opening of voltage gated Ca channels
2+
Ca promotes the exocytosis of acetylcholine containing vesicles
2+
Positive feedback of exocytosis
Opening of ion channel
+
Negative feedback of exocytosis
-
Sub-unit dissociation and downstream effects
Breakdown of ACh by acetylcholinesterase (AChE)
Reuptake of Choline
Pre-synaptic nicotinic ACh receptor
Post-synaptic nicotinic ACh receptor
Na
K
+
+
Pre-synaptic muscarinic ACh receptor
Post-synaptic muscarinic ACh receptor
Tyrosine
DOPA
Dopamine
Noradrenaline
Noradrenaline is packaged into vesicles via a hydrogen-coupled transporter (VMAT)
Arrival of action potential results in opening of voltage gated Ca channels
2+
Adenylate Cyclase synthesises cAMP which promotes Ca influx
2+
Ca promotes the exocytosis of acetylcholine containing vesicles
2+
Post-synaptic α-adrenoceptor
Pre-synaptic NA α2-receptor
Sub-unit dissociation and downstream effects
Sub-unit dissociation
inhibition of adenylate cyclase activity
decreased cAMP inhibits opening of calcium channels
Uptake 2
Uptake 1 (NET)
Breakdown of NA by monoamine oxidase
Uptake 2
Uptake 1
Breakdown of NA by monoamine oxidase
ACh is transported into synaptic vesicles via a specific transporter
Uptake of ACh is driven by movement of H+ down its electrochemical gradient (antiport system)
Transporter is inhibited by vesamicol (pharmacological tool)
ACh exocytosis is driven by the influx of calcium ions
Exocytosis also controlled by positive feedback from extracellular ACh acting on presynaptic receptors
Exocytosis of ACh is inhibited by botulinum

Possesses 2 sub-units
One binds selectively to cholinergic neurons enabling selective uptake of the toxin
Other subunit has protease activity, cleaves proteins important in docking of the synaptic vesicle to the pre-synaptic membrane
The action of acetylcholine in the synaptic cleft is terminated by acetylcholinesterase (AChE)
Inhibition of AChE causes an increase in ACh at the synaptic cleft prolonging its activity
Several therapeutic agents act by inhibiting cholinesterase activity eg. neostigmine, malathion
3 main groups:
Short-acting eg. edrophonium
Medium duration eg. neostigmine
Irreversible eg. malathion, dyflos
Possible anticholinesterase effects
Increase in twitch tension
Large doses can cause depolarization block
Overcomes neuromuscular block by non-depolarizing agents (eg. Tubocurarine)
Hemicholinium is a competitive inhibitor of the choline transporter
Depletes ACh in the nerve terminal (onset depends on size of stores and rate of use)
Triethylcholine is also a competitive inhibitor of the transporter
It is taken into the pre-synaptic terminal and leads to synthesis of a false transmitter (acetyltriethylcholine)
Neither drug used therapeutically
Tyrosine Hydroxylase
DOPA decarboxylase
Dopamine β-hydroxylase
β-adrenoceptor
eg. alpha-methyltyrosine (inhibitor)
eg. carbidopa (inhibitor)
eg. imipramine
cocaine
eg. prazocin (alpha1)
Agonist
eg. phenylephrine (alpha1)
eg. propranolol (non-selective)
Agonist
eg. isoprenaline (non-selective)
eg. yohimbine
eg. brimonidine
(nicotinic agonist)
Tubocurarine
(nicotinic antagonist)
(Muscarinic agonist)
Atropine
(muscarinic antagonist)
Full transcript