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PSYC 3030 (47)
Lecture 4

Week 4

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University of Guelph
PSYC 3030
Rob Foster

ACETYLCHOLINE Synthesis, storage & release Precursors: choline and Acetyl CoA Enzyme: choline acetyltransferase Products: acetylcholine and Coenzyme A Choline – two major sources 1. From diet – found in vegetables, egg yolk, kidneys, liver, seeds, and legumes. It enters the brain through specific carrier systems in the membrane of the capillary endothelial cells. This blood-brain barrier choline transporter is bidirectional. You can’t eat a lot of food containing choline, because there is a limit to the transport! 2. From previously released Ach – via a Na dependent high-affinity uptake mechanism. This mechanism is estimated to recycle 35 to 50% of all liberated choline back into Ach synthesis. Acetyl CoA = acetyl group + coenzyme A Synthesized in mitochondria (which contains coenzyme A) and derived from the metabolism of sugar and fats. Transport to cytoplasm is Ca dependent. Choline acetyltransferase (ChAT) Synthesized in the rER and transported via axoplasmic transport to the axon terminal. Most ChAT exist freely in the cytoplasm of nerve terminal. ChAT is considered to be a selective marker for cholinergic neurons (you can stain this enzyme to look for cholinergic neurons) There are 3 factors regulating ACh synthesis Product inhibition This as negative feedback system, where ACh binds to an allosteric binding site on ChAT, changing its 3D structure, and thus reducing its catalytic activity. Mass action The rate of ACh formation depends on the concentration of the precursor. There will be also an increased rate of production if there is a lot of release of acetylcholine (gap in the concentration, so the reaction goes faster). Thus, the administration of choline can enhance ACh synthesis, but only in Ach terminals that have been depleted because of ACh release. Neuronal activity ACh release increases ACh synthesis: 1) More ACh enters the vesicles from the cytoplasm 2) Increase in free choline in the synapse 3) Ca entrance in the terminal increases the rate of transport of acetyl CoA from the mitochondria to the cytoplasm. Acetylcholinesterase (AChE) It is responsible for acetylcholine breakdown into choline and acetic acid. There is no acetylcholine transporter, so you have to break it down so that the choline can be up taken by choline transporters. AChE is found in: 1- Pre-synaptic, in the cholinergic neuron 2- In the membrane of the post-synaptic cell 3- At neuromuscular junctions, released by muscle cells Drugs that affect ACh synthesis, storage, release, and inactivation Blockade of ACh synthesis - Some drugs can inhibit ChAT activity, but they are not selective. - Some drugs can inhibit the high-affinity choline transporter o Hemicholinium-3 (HC-3) – but it does not cross the BBB Blockade of ACh storage If you block the storage you also influence the release and synthesis. - Vesamicol inhibits the vesicular ACh transporter Blockade of ACh release - Botulinum Toxin (clostridium botulinum bacterium) – is very selective to cholinergic neurons; paralysis and asphyxiation - Tetanus Toxin (Clostridium tetani bacterium) – spastic paralysis, severe convulsions and death. Not quite selective to ACh as BT. Blockade of ACh inactivation Anticholinesterase agents increase the duration of action of ACh at cholinergic receptor sites by blocking ACh hydrolysis by AChE. In most cases, this is accomplished by competing with ACh for access to the active binding site of the AChE molecule. Reversible acetylcholinesterase inhibitors - Physostigmine (found in the seeds of a Nigerian plant) – readily crosses the BBB producing: slurred speech, confusion, loss of reflexes, convulsion, coma & death. - Neostigmine (a synthetic analog of Physostigmine, less lipid soluble) – does not cross the BBB and it is used clinically for the management of Myasthenia gravis, an autoimmune disorder whereby antibodies bind and eventually break down ACh receptors in muscles. Irreversible acetylcholinesterase inhibitors Synthetic organophosphorous compounds that form highly stable phosphorylated complexes with AChE that resist cleavage for hours or for ever! Your body tries to compensate making more enzyme, because there is no way of breaking that binding. - Parathion - used as an insecticide - Malathion – much less toxic to mammals and birds - Nerve gases – Sarin, Soman and tabum (II World War, Germany) – 1 mg or less, if inhaled, readily cross the BBB and cause intense sweating, filling of bronchial passages with mucus, bronchial constriction, dimmed vision, uncontrollable vomiting and defecation, convulsions, paralysis and death. Peripheral cholinergic systems Parasympathetic branch Preganglionic neuron = cholinergic neuron (releases ACh) – travels a long distance Postganglionic neuron = cholinergic neuron (releases ACh) Sympathetic branch Preganglionic neuron = cholinergic - their axons project for a relatively short distance before they synapse with sympathetic ganglia Postganglionic neuron = noradrenergic neuron (releases norepinephrine) Widespread involvement of ACh in both the neuromuscular and autonomic systems explains why drugs that interfere with this transmitter exert such powerful physiological effects and sometimes are highly toxic. Central cholinergic systems 1. Interneurons of the striatal complex - Small and medium neurons are found in this area - It works with the limbic system to control motivated behavior - The dorsal portion is involved in motor behavior 2. Projection neurons of the basal forebrain (BFCS) - All these regions have different locations and cholinergic groups - This region overall is known to be depleted of cholinergic cells in people with Alzheimer’s disease. o Rostral (anterior) basal forebrain: Ch1 – medial septum; Ch2 – vertical diagonal band of Broca o Medial basal forebrain: Ch3 – horizontal limb diagonal band of Broca o Caudal (posterior) basal forebrain: Ch4 – nucleus basalis and substantia innominate 3. Pontomesencephalic cell groups - Projections of posterior and anterior areas o Ch5 – peduncolopontine tegmental nucleus o Ch6 – laterodorsal tegmental nucleus Cholinergic receptors 1. Muscarinic receptors a. Activated by muscarine, an alkaloid found in a mushroom b. Their responses can be excitatory or inhibitory c. Their activation has long latency of onset (at least 100 ms) d. G protein-coupled receptors 2. Nicotinic receptors a. Activated by nicotine b. Their responses are always excitatory c. Their activation has a short latency (few ms) d. Ligand-gated channels (typically activated through a sodium channel) Nicotinic receptors - They can be homo or heteropentamers - Neuronal receptors and muscle receptors during fetal developme
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