Neurotransmiters of ans synthesis and fate


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Neurotransmiters of ans synthesis and fate

  1. 1. Topic : Neurotransmitters of ANS, their synthesis, release & fate Zulcaif Ahmad 1
  2. 2. Chemical Messengers • Four types of chemical messengers – Paracrines • Local chemical messengers • Exert effect only on neighboring cells in immediate environment of secretion site – Neurotransmitters • Short-range chemical messengers • Diffuse across narrow space to act locally on adjoining target cell (another neuron, a muscle, or a gland)
  3. 3. Chemical Messengers – Hormones • Long-range messengers • Secreted into blood by endocrine glands in response to appropriate signal • Exert effect on target cells some distance away from release site – Neurohormones • Hormones released into blood by neurosecretory neurons • Distributed through blood to distant target cells
  4. 4. of rview ve – O lism e rs a b o i t t et sm M an nd otr is a ur sNe the S yn 4
  5. 5. Definition A chemical released by one neuron that affects another neuron or an effector organ (e.g., muscle, gland, blood vessel)
  6. 6. R.E.B,, 2003 Neurotransmitters • Properties of neurotransmitters: 1) synthesized in the presynaptic neuron 2) Localized to vesicles in the presynaptic neuron 3) Released from the presynaptic neuron under physiological conditions 4) Rabidly removed from the synaptic cleft by uptake or degradation 5) Presence of receptor on the post-synaptic neuron. 6) Binding to the receptor elicits a biological response 6
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  8. 8. Neurotransmitters found in the nervous systemEXCITATORY Acetylcholine Aspartate Dopamine Histamine Norepinephrine Epinephrine Glutamate SerotoninINHIBITORY GABA 8 Glycine
  9. 9. Neurotransmitter of para sympathetic nervous system• Acetylcholine 9
  10. 10. Acetylcholine synthesis:• In the cholinergic neurons acetylcholine is synthesized from choline. This reaction is activated by cholineacetyltransferaseAs soon as acetylcholine is synthesized,it is stored within synaptic vesicles. 10
  11. 11.  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 Ca2+ concentration causes the synaptic vesicles that contain acetylcholine to fuse with the axonal membrane and open spilling their contents into the synaptic cleft. 11
  12. 12. Neurotransmitter Receptors in the ANS
  13. 13. CHOLINERGIC RECEPTORS • Acetycholine (Ach) action differs depending on the type of receptor it interacts with • Ach action is mimicked by nicotine in some organs and mimicked by muscarine in others  nicotinic cholinergic receptors muscarinic cholinergic receptors
  14. 14. Cholinergic Receptors • Nicotinic: Ligand-gated ion channels (+) allows entry of sodium and calcium ions • Muscarinic: G protein-coupled receptors (+) activate G proteins to induce downstream effects
  15. 15. Insert Brody Fig 8-10 p.98
  16. 16. Nicotinic Cholinergic Receptors • Primary action of Ach at P and S ganglia are mediated by activation of ganglionic NICOTINIC receptors (similar to that in the CNS and immune cells but different from that in the skeletal muscle at the NMJ) • These different types of nicotinic receptors allow for selective action (+ or -) of different agonist and antagonist
  17. 17. Muscarinic Cholinergic Receptors • Mediates responses to Ach at the parasympathetic neuroeffector junction • Subtypes M1 to M5: M1autonomic ganglia- modulates effects of nicotinic receptor activation M2 heart M3 glands, smooth muscles M4, M5?
  18. 18. Binding of acetylcholine to the postsynaptic receptors: 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. 21
  19. 19. Removal of Acetylcholine from the synaptic cleft: In order to ready the synapse for another impulses: 1) The neurotransmitters, which are released from the synaptic vesicles, are hydrolyzed by enzyme present in the synaptic cleft “Acetylcholinestrase” giving choline, which poorly binds to acetylcholine receptors. AcetylcholinestraseAcetylcholine + H2O Choline + H+ acetate 2) The empty synaptic vesicles, which are returned to the axonal terminal bulb by endocytosis, must be filled with acetylecholine. 22
  20. 20. Structure of AchE• Acetylcholinesterase (AchE) is an enzyme, which hydrolyses the neurotransmitter acetylcholine. The active site of AChE is made up of two subsites, both of which are critical to the breakdown of ACh. The anionic site serves to bind a molecule of ACh to the enzyme. Once the ACh is bound, the hydrolytic reaction occurs at a second region of the active site called the esteratic subsite. Here, the ester bond of ACh is broken, releasing acetate and choline. Choline is then immediately taken up again by the high affinity choline uptake system on the presynaptic membrane. 23
  21. 21. Neurotransmitters of sympatheticnervous system • Norepinephrine • Epinephrine 24
  22. 22. Catecholamine Synthesis (Dopamine, Norepinephrine and Epinephrine). 1) First Step: Hydroxylation: In this step: the reaction involves the conversion of tyrosine, oxygen and tetrahydrobiopterin to dopa & dihydrobiopterin. This reaction is catalyzed by the enzyme tyrosine hydroxylase. It is irreversible reaction. 2) Second step: Decarboxylation: In this step: the dopa decaboxylase will catalyze the decaoxylation of dopa to produce dopamine. The deficiency of this enzyme can cause Parkinson’s disease. It is irreversible reaction. The cofactor in this reaction is the PLP (pyridoxal phosphate). In the nerve cells that secrete dopamine as neurotransmitter the pathway ends at this step. 25
  23. 23. Catecholamine Synthesis (Dopamine, Norepinephrine and Epinephrine).3) Third step: Hydroxylation:This reaction is catalyzed by the enzyme dopamine β- hydroxylase. The reactants include dopamine, O2 and ascorbate (vitamin C).The products are norepinephrine, water and dehydroascorbate. Itis an irreversible reaction). The end product in noradrenergiccells is norepinephrine and the pathway ends her.4) Forth step: Methylation:This reaction is catalyzed by phenylethanolamine N-methyltransferase. Norepinephrine and S-adenosylmethionin(ado-Met) form epinephrine and S-adenosyl homocysteine (ado-Hcy). 26
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  26. 26. Epinephr COMT + ine MAO VanillylmandelicNorepineph acidrine COMT + Dopamin MAO Homovanillic e acid Neuronal re-uptake and degradation of catecholamines quickly terminates hormonal or neurotransmitter activity. Cocaine binds to dopamine receptor to block re- uptake of dopamineFigure 3. Degradation of epinephrine, norepinephrine and dopamine Dopamine continues to stimulate receptors of thevia monoamine oxidase (MAO) and catechol‑O‑methyl-transferase postsynaptic nerve.(COMT)
  27. 27. Adrenergic Receptors • NE and Epi can activate more than one type of adrenergic receptor • β receptors (1,2, and 3 subtypes) ∀ α1 (3 subtypes) and α2 (3 subtypes)
  28. 28. Prejunctional autoreceptors • Prejunctional α2 receptors are present in adrenergic and cholinergic nerve terminals • Activation of these result to decrease in further release of NTS presynaptic inhibitory autoreceptor mechanism (regulatory function)
  29. 29. Figure 2. Regulation of the Stressrelease of catecholamines Chronic Hypothalamusand synthesis of epinephrine regulationin the adrenal medulla ACTHchromaffin cell. from adrenal Cortisol cortex via intra- Tyrosine adrenal portal system Acute L- DP regulation Dopa N induction granu DPN Neuron .... .... ... ... . Ca2+ le ↓ NE ... N PNMT Epinephrine ⊕ E E E E acetylcholine neuro- promot NE E es secret Adrenal exocyt E E ory Medulla osis EEE ENE granul Chromaffin EE es Cell NE
  30. 30. Table 1. Classification of Adrenergic Hormone Receptors Second Receptor Agonists G protein Messenger alpha1 (α1) E>NE IP3/Ca2+; DAG Gq alpha2 (α2) NE>E ↓ cyclic AMP Gi beta1 (β1) E=NE ↑ cyclic AMP Gs beta2 (β2) E>>NE ↑ cyclic AMP Gs E = epinephrine; NE = norepinephrine Synthetic agonists: isoproterenol binds to beta receptors phenylephrine binds to alpha receptors (nose spray action) Synthetic antagonists: propranolol binds to beta receptors phentolamine binds to alpha
  31. 31. β1 or β2 α2 receptor receptor Gs Gi αs β αi β γ β β γ γ γ GTP GTP αi αs GTP GTP ⊕  inactive ACTIVE X inactive adenylyl adenylyl cyclase adenylyl cyclase cyclase ATP cyclic AMPFigure 5. Mechanisms of β1, β2, and α2 agonist effects on adenylylcyclase activity
  32. 32. Role of cyclic AMP second messenger pathway
  33. 33. Other Neurotransmitters:Neurotransmitter Derived from EnzymeHistamine Histidine Histidine decarboxylaseGABA Glutamate Glutamate(γ-Amino decarboxylasebutyrate)Nitric Oxide Arginine Nitric Oxide Synthase 37
  34. 34. Summary: Neurotransmitter Derived Site of Synthesis Molecule From Acetylcholine Choline CNS, parasympathetic nerves   Serotonin Tryptophan CNS, chromaffin cells of the gut, enteric 5-Hydroxytryptamine (5-HT) cells GABA Glutamate CNS Histamine Histidine hypothalamus Epinephrine Tyrosine adrenal medulla, some CNS cells synthesis pathway Norpinephrine Tyrosine CNS, sympathetic nerves synthesis pathway Dopamine Tyrosine CNS synthesis pathway Nitric oxide, NO Arginine CNS, gastrointestinal tract
  35. 35. Original Dale’s Law (1950’s) “A mature neuron makes use of the same transmitter substance at all of its synapses” Discovery of peptide transmitters Modified Dale’s Law = “A mature neuron makes use of the same combination of chemical transmitters at all of its synapses.”
  36. 36. Modified Dale’s Law – when co- secretion occurs, itusually involves a small molecule transmitter and oneor more peptides Small Molecule Transmitter Peptide AcH VIP Norepinephrine Somatostatin + enkephalin + neurotensin Dopamine Cholecystokinin + enkephalin Epinephrine Enkephalin Substance P + TRH Serotonin