A5. Cholinergic transmission and its presynaptic modification.

Question 1

List the steps in Cholinergic transmission.

Answer 1

1. Synthesis: Acetyl-CoA + choline → Acetylcholine via Choline Acetyltransferase (ChAT).
2. Storage: Acetylcholine transported into vesicle via vesicle-associated transporter (VAT) which is an Ach/H+ antiporter. Inhibited by vesamicol
3. Release: calcium influx causes action potential → Ach in synaptic cleft. This step is inhibited by botulinum toxin.
4. Reception/recognition: Ach acts on postsynaptic muscarinic or nicotinic receptors, also some presynaptic receptors on the neuron
5. Termination: Acetylcholinesterases or pseudocholinesterases hydrolyze Ach into choline and acetate
6. Recycling: choline is taken back up into the neuron. This is probably the rate limiting step. Inhibited by hemicholinium.

Question 2

What type of cholinergic receptors do we have

Answer 2

1. Nicotinic
2. Muscarinic

Question 3

What are nicotinic receptors?

Answer 3

Nicotinic receptors are ionotropic receptor – allows ions (Na+, K+) to cross membrane. Fast-acting when compared to muscarinic receptors.

Question 4

What type of nicotinic receptors do we have?

Answer 4

1. N_M (muscular) type: causes excitatory post-synaptic potential (EPSP) → stimulation of NMJ; skeletal muscle activation. Blockers used for paralysis during surgery.
2. N_N (neuronal) type: preganglionic activation of both parasympathetic and sympathetic nervous system. Epinephrine released from adrenal medulla. Generally not safe to modify these clinically.

Question 5

What are muscarinic receptors?

Answer 5

Muscarinic receptors are G-protein coupled receptors. Slower. There are 5 of them, but only the first 3 are well-understood and more important to know. Mostly part of the parasympathetic nervous system, except for sweat glands with sympathetic nervous system.

Question 6

What are the different types of muscarinic receptors and there effects?

Answer 6

Agonism of muscarinic receptors causes these effects:

1. M1: increased gastric acid secretion
2. M2: inhibits cardiac activity, causes AV block
3. M3: Bronchoconstriction, GI secretions and motility associated with digestion. Vasodilation: M3 receptors are on blood vessels, but parasympathetic nervous system does not innervate them. Can only be reached through contact with direct muscarinic agonists.

Question 7

List the drugs that cause presynaptic modification.

Answer 7

These are all inhibitors of some part of the Ach cycle

1. Inhibitors used in research: These drugs aren’t clinically useful. They non-selectively decrease acetylcholine production → weaker activation of skeletal muscle + anti-sympathetic + anti-parasympathetic effects. These drugs include Vesamicol which inhibits VAT and Hemicholinium which decreases choline uptake.
2. Botulinum toxin: cleaves SNARE proteins, preventing release of the Ach-containing vesicle. Causes flaccid paralysis when injected into muscle. If absorbed systemically → general paralysis. Can be lethal via respiratory muscle paralysis. Injected into facial muscles to reduce wrinkles (botox). Can be used clinically to treat some spastic muscle disorders or dystonia.
3. α-latrotoxin (α-LTX): black widow spider toxin. Less important to know than the others. Causes excessive release of Ach into the nerve terminal.

Question 8

What are Ganglion blockers?

Answer 8

These agents are antagonists of neuronal-type nicotinic receptors (therefore in the ganglion).

Question 9

What are the different types of ganglion blockers that we have?

Answer 9

Depolarizing and Non-depolarizing

Question 10

What are the depolarizing ganglion blockers?

Answer 10

1. Nicotine: normally an agonist of nicotinic receptors (as the name suggests), but at high doses it functions as a depolarizing ganglion blocker, causing blood pressure to fall as it inhibits the ANS.

Question 11

What are the Non-depolarising ganglion blocker?

Answer 11

These were the first successful treatments for hypertension, but there are much better drugs out there now.

1. Hexamethonium: the first one.This drug is a quaternary amine, meaning it has an N+ somewhere in the structure that makes it more water soluble and absorbs poorly in the GI tract. Tetraethylammonium: less important, similar drug
2. Mecamylamine: this is a tertiary amine, meaning it has a neutral N in the structure. Was developed to absorb better in the GI tract. Trimethaphan: less important, similar drug. (Surgeries to lower blood pressure).

Question 12

What are the effects of ganglion blockers?

Answer 12

These drugs nonspecifically inhibit both sympathetic and parasympathetic nervous systems, leading to these mixed effects (depending on whether parasympathetic or sympathetic system is dominant in a particular organ.

Some of the major affects are:

1. Vasodilation: sympathetic system inhibited. Can cause hypotension.
2. Tachycardia: parasympathetic tone normally dominant in the heart. Inhibition → HR ↑
3. Assorted parasympathetic effects: mydriasis (pupil dilation), constipation, urinary retention, xerostomia (dry mouth)
4. Sympathetic: anhydrosis (lack of sweat)