BIOSYNTHESIS OF ACETYLCHOLINE IN CNS AND CHOLINERGIC TRANSMISSION

1. BIOSYNTHESIS OF ACETYLCHOLINE IN CNS AND CHOLINERGIC TRANSMISSION BY ADESEJI, WASIU ADEBAYO ( B.Sc Hons ) 08/46KA006 ANA 808: ADVANCED NEURONATOMY DEPARTMENT OF ANATOMY, UNIVERSITY OF ILORIN. JULY, 2015. Lecturer : DR O. B. AKINOLA ( P.hd )

2. OUTLINE INTRODUCTION SYNTHESIS OF ACH CHOLINERGIC TRANSMISSION CHOLINERGIC RECEPTORS CONCLUSION REFERENCES 2

3. INTRODUCTION Acetylcholine ( 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. 3

4. 4

5. 5

6. 6

7. 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. 7

8. SYNTHESIS OF ACH 8

9. SYNTHESIS OF ACH ACh 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. Ca 2+ appears to be involved in both of these regulatory mechanisms. 9

10. SYNTHESIS OF ACh ACh 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 . 10

11. 11

12. 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 Ca 2+ ions to pass from the synaptic cleft into the axon bulb. 2)    Within the bulb the increase in Ca 2+ concentration causes the synaptic vesicles that contain acetylcholine to fuse with the axonal membrane and open spilling their contents into the synaptic cleft. 12

13. 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. 13

14. 14

15. 15

16. Muscarinic receptor Features M1 M2 M3 Location Autonomic and enteric ganglia Paracrine cell gastric gland CNS 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

17. Eyes : contraction of ciliary muscle and smooth muscle of the iris sphincter ( miosis ) Hear t : Bradycardia (possibly preceded by tachycardia ), decrease force of conytraction Blood 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

18. Acetycholine : nicotinic action Neuro -muscular Junction : nicotinic Nm receptor Stimulation lead to muscle contraction Sympathetic And P. Sympathetic Ganglia : Nn receptor Release of NE and Ach Adrenal Medulla : Nn receptor Release of adrenaline

19. 19

20. Location Of Ach Receptor Nicotinic receptor Neuromuscular junction All the autonomic ganglia In the brain Muscarinic receptor Parasympathetic neuro-effector junction M1 – sympathetic ganglia , gastric parietal cell , cerebral cortex(+) M2 – myocardium , smooth muscle (-), presynaptic nerve terminal M3- glandular and visceral smooth muscle (+)

21. 21 THANK YOU FOR LISTENING