Peripheral neural transmission: Cholinergic (nicotinic) transmission

Question 1

Hemicholium

Answer 1

Blocks transporter that transports choline into nerve cell

Question 2

Vesamicol

Answer 2

Non-competitive, reversible blocker of VAChT (SLC18A3)

Question 3

ACh storage vesicles

Answer 3

Appear electron-lucent in electron micrographs.
Contain ACh:ATP in ration 10:1
Estimates of ACh content of vesicles range 1,000 to >50,000 molecules

Question 4

VIP storage vesicles

Answer 4

Dense-cored

Found in some cholinergic nerves

Question 5

Botulinum toxin

Answer 5

Blocks ACh release by cleaving target SNARE

May lead to respiratory failure

Question 6

beta-bungaratoxin

Answer 6

Blocks ACh release
Acts through a phospholipase A2 rather than peptidase activity
Localises to the membrane by a K+ channel binding moiety

Question 7

alpha-latrotoxin

Answer 7

Venom of black widow spider
Binds to neurexins (TM proteins on nerve PM)
Causes massive release of ACh

Question 8

BuChE (butyrylcholinesterase)

Answer 8

Much broader substrate specificity than AChE
Also breaks down LA procaine
Made in the liver, found mainly in plasma

Question 9

AChE

Answer 9

Relatively specific for ACh
Found in :
synaptic cleft (3 tetramers of AChE attached by disulphide bonds to collagenous tail. Tail localises the enzyme by binding to a heparan sulphate proteoglycan in the basement membrane. Each tetramer cluster contains 12 sites for ACh hydrolysis- can breakdown ACh within c.1ms)
presynaptic nerve terminal (soluble)

Question 10

alpha-bungarotoxin

Answer 10

Irreversible antagonist of nicotinic ACh R at n.m.j. Also affects brain (a7)5 isoform

Question 11

Hexamethonium

Answer 11

Channel pore blocker of nicotinic ACh R.

Use-dependent blockage of ganglionic transmission.

Question 12

d-tubocurarine

Answer 12

Purified product of curare
Agonist at nicotinic ACh R -> depolarizing block
Relatively non-selective between ganglion & n.m.j at clinical doses
Quaternary ammonium compound- not orally active

Question 13

Atracurium

Answer 13

Competitive antagonist at n.m.j nicotinic ACh R.
(non-depolarizing blocker)
Quaternary ammonium compound- not orally active
Ester- broken down by spontaneous hydrolysis and plasma esterases

Question 14

Pancuronium

Answer 14

Competitive antagonist at n.m.j nicotinic ACh R.
(non-depolarizing blocker)
Quaternary ammonium compound- not orally active
Longer action than atracurium, not hydrolyses

Question 15

Selective non-depolarising neuromuscular blocking agents

Answer 15

Atracurium and pancuronium
Competitive antagonists of nicotinic R
Cause ‘tetanic fade’-thought to be due to block of nicotinic ‘autoreceptors’ which give positive feedback to maintain transmitter release.
Used in anaesthesia to produce muscle relaxation (affect fast ‘white’ > slow ‘red’)
Reversed by anticholinesterases

Question 16

Nicotine

Answer 16

Depolarising blocker (long acting agonist) at ganglionic nicotinic ACh receptors

Question 17

Decamethonium

Answer 17

Depolarising blocker (long acting agonist) of nicotinic ACh R
Selective for n.m.j form

Question 18

Suxamethonium

Answer 18

Depolarising blocker (long acting agonist) of nicotinic ACh R. Selective for n.m.j form 
Very short duration of action, used in intubation. 
Ester, broken down by plasma BuChE

Question 19

Depolarising block and AChEs

Answer 19

In phase I (inactivation of VGNaC): AChEs deepen blockade. Can be opposed by non-depolarising blockers
In phase II (desensitisation of nicotinic R): AChEs reverse blockade

Question 20

Atropine

Answer 20

Muscarinic antagonist

Question 21

Muscarine

Answer 21

Muscarinic agonist

Question 22

Acetyl-β-methylcholine aka methacholine

Answer 22

Muscarinic agonist
2 isomers: neither is hydrolysed by BuChE
(+)methacholine is a substrate for AChE, and ~200x more potent than (-) isomer at muscarinic receptors. (-) isomer has no affinity

Question 23

Isoprenaline (compare to Acetyl-β-methylcholine)

Answer 23

β-adrenoceptor agonist

Inactive isomer has affinity, but no efficacy.

Question 24

Benzylcholine mustard

Answer 24

Irreversibly alkylates the muscarinic receptor
Introduces the concept of spare receptors or receptor reserve- as progressively reacts with receptors, at first a maximum response with ACh is still attainable. Parallel shift of log concentration/ response curve.

Question 25

Trimetaphan

Answer 25

Competitive antagonist

Selective for ganglionic form of nicotinic receptor