BIOSYNTHESIS OF ACETYLCHOLINE IN CNS AND CHOLINERGIC

TRANSMISSIONBY

ADESEJI, WASIU ADEBAYO (B.Sc Hons)08/46KA006ANA 808: ADVANCED NEURONATOMY

DEPARTMENT OF ANATOMY,UNIVERSITY OF ILORIN.JULY, 2015.

Lecturer: DR O. B. AKINOLA (P.hd)

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OUTLINE INTRODUCTION SYNTHESIS OF ACH CHOLINERGIC TRANSMISSION CHOLINERGIC RECEPTORS CONCLUSION REFERENCES

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INTRODUCTIONAcetylcholine (ACh), the first neurotransmitter discovered, was originally described as "vagus stuff" by Otto Loewi because of its ability to mimic the electrical stimulation of the vagus nerve.It is now known to be a neurotransmitter at all autonomic ganglia, at many autonomically innervated organs, at the neuromuscular junction, and at many synapses in the CNS. Ach is a small-molecule excitatory neurotransmitter with a wide variety of known functions

Within the central nervous system (CNS), cholinergic cells (neurons that use ACh as a neurotransmitter) are found in several different locations of the brain, including the striatal complex, the basal forebrain, the diencephalon, pontomesencephalic cell groups, and the medulla.

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Depending on which area of the brain it is found in, ACh may be involved in any one of several different functions. Some of these functions include the conduction of pain, the regulation of neuroendocrine function, the regulation of REM sleep cycles, and the process of learning and memory formation.Within the basal forebrain, it is the cholinergic cells of the septal nuclei that play a large role in learning and memory. These neurons send major projections to the hippocampus, a structure particularly important for the normal formation of declarative memories. Several noteworthy clinical cases have shown that lesions in this area of the brain alone can greatly impair an individual's ability to form new declarative memories. It is this cholinergic system, among others, that has been shown to suffer serious neurodegeneration in Alzheimer's disease, a condition characterized by a significant failure of memory and other cognitive functions.

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SYNTHESIS OF ACH

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SYNTHESIS OF ACHACh is made up of choline and acetate. These precursors must be readily available to the neuron terminal at all times so that ACh can be synthesized whenever it is needed.Choline is a compound that can be obtained from foods such as egg yolks, kidney, liver, seeds, legumes, and various vegetables. It is also naturally produced by the liver. Free choline circulating in blood plasma readily crosses the blood-brain barrier and is taken up by cholinergic nerve terminals, for the most part, by a high-affinity choline uptake (HACU) system that is temperature-, energy- and sodium-dependent.The rate-limiting steps in ACh synthesis are the availability of choline and acetyl-CoA. During increased neuronal activity the availability of acetyl-CoA from the mitochondria is upregulated as is the uptake of choline into the nerve ending from the synaptic cleft. Ca2+ appears to be involved in both of these regulatory mechanisms.

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SYNTHESIS OF ACHACh is an example of an excitatory small-molecule neurotransmitter.Small-molecule neurotransmitters are synthesized locally within the axon terminal.The synthesis of ACh requires the enzyme choline actyltransferase and, like all small-molecule neurotransmitters, takes place within the nerve terminal.

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CHOLINERGIC TRANSMISSION

1)When the nerve impulse (Action potential) moves down the presynaptic axon to the terminal bulb the change in the membrane action potential causes the opening of voltage gated calcium channels open allowing Ca2+ ions to pass from the synaptic cleft into the axon bulb.

2)  Within the bulb the increase

in Ca2+ concentration causes the

synaptic vesicles that contain

acetylcholine to fuse with the

axonal membrane and open

spilling their contents into

the synaptic cleft.

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CHOLINERGIC TRANSMISSION The postsynaptic membrane of the receptor dendrite has specific cholinergic receptors toward which the neurotransmitter diffuses. Binding of acetylcholine trigger the opening of ion channels in the postsynaptic membrane initiating action potential that can pass in the next axon.

Acetylcholine receptors: Acetylcholine receptors are ion channels receptors made of many subunits arranged in the form [(α2)(β)(γ)(δ)].

When Acetylcholine is not bounded to the receptors, the bulky hydrophobic leu side close the central channels preventing the diffusion of any ions.

Binding of two acetylcholine molecules to the receptors will rotate the subunits in which the smaller polar residues will line the ion channel causing the influx of Na+ into the cell and efflux of K+ resulting in a depolarization of the postsynaptic neuron and the initiation of new action potential.

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MUSCARINIC RECEPTOR Features M1 M2 M3

Location Autonomic and enteric ganglia Paracrine cell gastric glandCNS

SA node , AV node , presynaptic terminal

Exocrine gland , smooth muscle , vascular endothelium

Function Gastric acid Cns excitation Gi motility

Dercrase rate of impulse generation Velocity of conduction Bradycardia contractility

Increase in exocrine secretion , smooth muscle contraction

Mechanism ip3 , DAG , increase in ca 2+ conc.

Inhibition of adenyl cyclase , decrease CAMP opening of k+ channel

Same as the M1 receptor

Agonist Oxotremorine Methacholine Bethacholine Antagonist Pirenzepine

Telenzepine Triptramine Tolterodine

Darifenacin

Eyes: contraction of ciliary muscle and smooth muscle of the iris sphincter (miosis) Heart : Bradycardia (possibly preceded by tachycardia), decrease force of conytractionBlood vessel : vasodilation ( EDRF) Lung : bronchoconstriction and increase secretion Pancreas : increased pancreatic juice Urinary bladder : voiding of urine ( detrusor and spincter) Sweat gland : increased sweating

ACETYLCHOLINE – MUSCARINIC ACTION

ACETYCHOLINE : NICOTINIC ACTION Neuro-muscular Junction: nicotinic Nm receptor Stimulation lead to muscle contraction

Sympathetic And P. Sympathetic Ganglia: Nn receptorRelease of NE and Ach

Adrenal Medulla : Nn receptor Release of adrenaline

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LOCATION OF ACH RECEPTOR

Nicotinic receptor 1. Neuromuscular junction 2. All the autonomic ganglia3. In the brain Muscarinic receptor Parasympathetic neuro-effector junction 4. M1 – sympathetic ganglia , gastric parietal cell , cerebral

cortex(+) 5. M2 – myocardium , smooth muscle (-), presynaptic

nerve terminal 6. M3- glandular and visceral smooth muscle (+)

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