Learning Objectives: Cholinergic Synaptic Communication

BIOSYNTHESIS Know the assembly of choline molecule and the rate limiting component for choline acetyl transferase. Recognize the significance of the high affinity choline transfer mechanism. Understand the effect of Hemicholinium on the availability of acetylcholine. Phosphatidyl ethanolamide is made to phosphatidyl choline is made to choline is made to acetylcholine by choline acetyl transferase (CAT). Rate limiting agent is choline. Hemicholinium inhibits reuptake of choline from synaptic cleft so it cannot be recycled. This results in deficiency since production is slow.

TOXIC MECHANISMS Know the mechanism of toxicity for curare, black widow spider, Botulinum toxin [CNS is not involved], Tetanus toxin [brain stem is involved]. Curare is an antagonist of nAchR that causes flaccid paralysis. Black Widow venom causes a massive rapid release of Ach to overstimulate the postsynaptic neuron (tetany) Botulinum toxin blocks the release of Ach from presynaptic neurons by using a zinc peptidase to destroy the synaptic vesicle fusing apparatus. Tetanus toxin goes to the brainstem and inhibits release of glycine and GABA (inhibitory transmitters) by the same zinc peptidase mechanism, resulting in too much contraction.

BREAK DOWN Acetyl choline esterase please concentrate on pharmacology lectures. Remember: sarin and physostigmine. Ach Esterase breaks down about half of all Ach in the cleft; the rest is recycled. Sarin and Physostigmine inhibit AchEsterase and increase the time of action of Ach in the cleft.

NICOTINIC RECEPTORS Gated Na ion-channels made from five subunits. Review pharmacology lectures. These receptors have an open and closed configuration; they can also be desensitized [usually when over stimulated]. Cytoplasmic phosphorylation is a fine tuning mechanism for these receptors. Different haplotypes are available for each subunit which can result in the generation of a large variety of receptors in different tissues at different developmental stages. Be aware that smoking may influence the subunit structures of receptors in the CNS. Alpha4beta2 upregulated in brains of smokers Smoking and the risk of nicotine dependence are under genetic [and cultural] influences. Even the capacity to quit smoking is influenced by nine different genes. MUSCARINIC RECEPTORS Please review pharmacology lectures. These receptors are also present in a large variety and all are using second messengers. They produce slower and longer lasting effects. Muscarine is an agonist; atropine is an antagonist (anticholinergic). NEW DEVELOPMENTS Nicotine may have pharmacological relevance to certain disorders like attention deficit. Vaccination against nicotine polymers may benefit some smokers.