Lecture 15 Cholinergic Transmission

Lecture 15 Cholinergic 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 NICOTINIC • Stimulation of all parasympathetic MUSCARINIC pathways. • Stimulates secretion of adrenaline from the NICOTINIC adrenal medulla • From the last lecture: Do you remember which receptors are involved?

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

glucose

glucose The Cholinergic Synapse

pyruvate

ChAT

CHOLINE +AcCoA

ACh + HSCoA

CHOLINE M2 receptor ACh

CHOLINE + ACETATE

AChE M1 receptor

nAChR

Acetylcholine Vesicular Transporter + H ATP ADP

H+

ACh

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

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 choline uptake), 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 lacrimal glands. 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, biliary and 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

Table 7.2 page 119, Rang, Dale and Ritter

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.