Lecture 15Cholinergic Transmission

Rang, Dale and Ritter, 5th Edition, Chapter 10

Learning Objectives

• Describe the synthesis, storage and release of acetylcholine and how drugs can interact with these pathways in the ANS

• Describe the nicotinic receptors• Describe the muscarinic receptors and their

locations.• Describe the effects and major clinical uses

of drugs affecting the cholinergic system.

Where Does Acetylcholine Act?

• Stimulation of all autonomic ganglia• Stimulation of all parasympathetic

pathways.• Stimulates secretion of adrenaline from the

adrenal medulla• From the last lecture: Do you remember

which receptors are involved?

.

NICOTINIC

NICOTINIC

MUSCARINIC

Classification of ACh Receptors

• Actions that can be produced by MUSCARINE – the active ingredient of the poisonous mushroom Amanita muscarineand can be abolished by small doses of ATROPINE (generally correspond to parasympathetic stimulation.)

• Actions that can be produced by nicotine.

CHOLINE +AcCoA ACh + HSCoAChAT

ACh

AChE

CHOLINE + ACETATE

M1 receptor nAChR

M2receptor

CHOLINE

glucose

pyruvate

glucose

The Cholinergic Synapse

Acetylcholine Vesicular Transporter

• ACh transport is coupled to an electrochemical gradient for protons.

• Blocked with vesamicol.

H+

H+

ATP ADP

ACh

Possible Sites of Drug Action:• Mimic (nicotinic or muscarinic agonists) or

prevent (antagonists) the action of Ach on the receptor

• prevent the synthesis of Ach (prevents cholineuptake), e.g. hemicholinium

• prevent the release of Ach, e.g. botulinium toxin (Botox), or Ca2+ channel blockers

• Enhance the release, e.g. 4-aminopyridine • prevent the vesicular storage, e.g. vesamicol• prevent the breakdown of Ach, e.g. neostigmine

Nicotinic Receptors

• Divided into two classes – muscle (Nm) and neuronal (Ng)

• Muscle receptors occur at the skeletal neuromuscular junction (non ANS, but will discuss in next lecture)

• Neuronal occur in autonomic ganglia and in the brain

• All are ligand gated ion channels – MoA 3 lecture (Lecture 12).

Nicotinic Receptors

• Activation causes increased cell permeability to sodium and potassium ions

• Increase in cations inside the cell leads to depolarisation of the postsynaptic membrane

• This results in a fast excitatory postsynaptic potential at the ganglionic synapse.

Nicotinic Receptors Are Subject to Depolarising Blockade

• In addition to blockade by an antagonist –nicotinic receptors can also be inactivated by prolonged agonist exposure

• Application of nicotine to a sympathetic ganglion initially causes an action potential discharge, after a few seconds this discharge ceases and transmission is blocked, after time the cell will repolarise, but transmission remains blocked

Depolarising Blockade

• This is caused by two mechanisms:– Voltage sensitive Na+ channels become

refractory and no long able to open in response to a brief depolarising stimulus

– Even after the cell has repolarised receptor desensitization occurs

Drugs Acting At Nicotinic Receptors

• Ng – don’t make very useful drug targets due to widespread distribution throughout the ANS. Experimental tools such as DMPP (agonist).

• Nm – muscle relaxants (for anaesthesia) –pancuronium or suxamethonium(depolarising).

Muscarinic Receptorss

• 5 receptors have been cloned M1-M5• All are G-protein coupled receptors• M1, M3 and M5 – Gq (what second

messengers would be activated?)• M2, M4 – Gi/o• Only M1, M2 and M3 have been well

characterised

Muscarinic Actions

• Stimulation of exocrine glands such as sweat, salivary, mucous and lacrimalglands. Gastric, intestinal and pancreatic sections are also increased (partially due to parasympathetic input) (M3)

• Stimulation of smooth muscle contraction in bronchi, GI tract, gall bladder, bileduct, urinary bladder and ureters (M3)

Muscarinic Actions (cont’d)

• Stimulation of the circular muscles of the iris and muscles of accommodation (pupil constricts, lens accommodated to near vision) – M3

• Relaxation of sphincters in the GI, biliaryand urinary tracts.

• Slowing of the heart. (M2)

Most Agonists/Antagonists Are Non-selective

• Agonists: – Muscarine– Pilocarpine– Bethanechol– McNA343 and oxotremorine are selective for M1

receptors, while carbachol is relatively inactive on M1.

• Antagonists:– Atropine– Scopolamine– M1 antagonist: pirenzipine– M2 antagonist: gallamine

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Nicotinic Cholinergic

Synapse

Cholinergic Muscarinic Synapse

• Difference from previous slide:– Presynaptic receptors and post synaptic

receptors are muscarinic. Presynaptic MUSCARINIC receptors serve to INHIBIT further release of Ach.

– Therefore, muscarinic agonists & antagonists rather than nicotinic ones, e.g. Ach & atropine respectively should be used as examples.