NEUROBIOCHEMISTRY

1. NEUROBIOCHEMISTRY SYNAPSE AND NEUROTRANSMITTER MOHAMMAD HANAFI

2. Synapses • A junction that mediates information transfer from one neuron: • To another neuron • To an effector cell • Presynaptic neuron – conducts impulses toward the synapse • Postsynaptic neuron – transmits impulses away from the synapse

3. The Synapse • Junction between two cells • Site where action potentials in one cell cause action potentials in another cell • Types of cells in synapse • Presynaptic • Postsynaptic

4. Synapses Axodendritic synapse Axosomatic synapse Axoaxonic synapse Figure 11.17

5. Electrical Synapses • Gap junctions that allow local current to flow between adjacent cells. Connexons: protein tubes in cell membrane. • Found in cardiac muscle and many types of smooth muscle. Action potential of one cell causes action potential in next cell, almost as if the tissue were one cell. • Important where contractile activity among a group of cells important.

6. Chemical Synapses • Components • Presynaptic terminal • Synaptic cleft • Postsynaptic membrane • Neurotransmitters released by action potentials in presynaptic terminal • Synaptic vesicles: action potential causes Ca 2+ to enter cell that causes neurotransmitter to be released from vesicles • Diffusion of neurotransmitter across synapse • Postsynaptic membrane: when ACh binds to receptor, ligand-gated Na+ channels open. If enough Na+ diffuses into postsynaptic cell, it fires.

7. Chemical Synapse Events at a chemical synapse 1. Arrival of nerve impulse opens volage-gated calcium channels. 2. Ca++ influx into presynaptic term. 3. Ca++ acts as intracellular messenger stimulating synaptic vesicles to fuse with membrane and release NT via exocytosis. 4. Ca++ removed from terminal by mitochondria or calcium-pumps. 5. NT diffuses across synaptic cleft and binds to receptor on postsynaptic memb 6. Receptor changes shape of ion channel opening it and changing membrane potential 7. NT is quickly destroyed by enzymes or taken back up by astrocytes or presynaptic membrane. Note: For each nerve impulse reaching the presynaptic terminal, about 300 vesicles are emptied into the cleft.

8. Neurotransmitter Removal • Method depends on neurotransmitter/synapse. • ACh: acetylcholinesterase splits ACh into acetic acid and choline. Choline recycled within presynaptic neuron. • Norepinephrine: recycled within presynaptic neuron or diffuses away from synapse. Enzyme monoamine oxidase (MAO). Absorbed into circulation, broken down in liver.

9. Removal of Neurotransmitter from Synaptic Cleft

10. Receptor Molecules and Neurotransmitters • Neurotransmitter only "fits" in one receptor. • Not all cells have receptors. • Neurotransmitters are excitatory in some cells and inhibitory in others. • Some neurotransmitters (norepinephrine) attach to the presynaptic terminal as well as postsynaptic and then inhibit the release of more neurotransmitter.

11. Neurotransmitters found in the nervous system EXCITATORY Acetylcholine Aspartate Dopamine Histamine Norepinephrine Epinephrine Glutamate Serotonin INHIBITORY GABA Glycine

12. Neurotransmitters • Chemicals used for neuronal communication with the body and the brain • 50 different neurotransmitters have been identified • Classified chemically and functionally • Chemically: • ACh, Biogenic amines, Peptides • Functionally: • Excitatory or inhibitory • Direct/Ionotropic (open ion channels) or Indirect/metabotropic (activate G-proteins) that create a metabolic change in cell

13. Chemical Neurotransmitters • Acetylcholine (ACh) • Biogenic amines • Amino acids • Peptides • Novel messengers: ATP and dissolved gases NO and CO

14. Neurotransmitters: Acetylcholine • First neurotransmitter identified, and best understood • Released at the neuromuscular junction • Synthesized and enclosed in synaptic vesicles • Degraded by the enzyme acetylcholinesterase (AChE) • Released by: • All neurons that stimulate skeletal muscle • Some neurons in the autonomic nervous system • Binds to cholinergic receptors known as nicotinic or muscarinic receptors • Nicotinic receptors • Neuromuscular junction of skeletal muscles

15. Acetylcholine synthesis: • In the cholinergic neurons acetylcholine is synthesized from choline. This reaction is activated by cholineacetyltransferase As soon as acetylcholine is synthesized, it is stored within synaptic vesicles.

16. Structure of AchE • Acetylcholinesterase (AchE) is an enzyme, which hydrolyses the neurotransmitter acetylcholine.The active site of AChE ismade up oftwo subsites, both of which are critical to the breakdown of ACh. Theanionic siteserves 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 calledthe 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.

19. Cholinergic Receptors • Nicotinic receptors - On neuromuscular junction of skeletal muscle - On all ganglionic neurons of autonomic nervous system - Excitatory • Muscarinic receptors - All parasympathetic target organs (cardiac and smooth muscle) - Exciatory in most cases

20. Acetylcholine Effects prolonged (leading to tetanic muscle spasms and neural “frying”) by nerve gas and organophosphate insecticides (Malathion). ACH receptors destroyed in myasthenia gravis Binding to receptors inhibited by curare (a muscle paralytic agent-blowdarts in south American tribes) and some snake venoms.

21. FUNCTIONS OF ACh • Acetylcholine is involved in a variety of functions • including pain, recent memory, nicotine addiction, salivation, locomotion, regulation of circadian rhythm and thermoregulation. 2. It has also been demonstrated that brain cholinergic neurons play a critical role in Alzheimer’s disease, Huntington’s chorea and in the generation of epileptic seizures.

22. Neurotransmitters: Biogenic Amines • Include: • Catecholamines – dopamine, norepinephrine (NE), and epinephrine (EP) • Indolamines – serotonin and histamine • Broadly distributed in the brain • Play roles in emotional behaviors and our biological clock

23. Synthesis of Catecholamines • AA tyrosine parent cpd • Enzymes present in the cell determine length of biosynthetic pathway • Norepinephrine and dopamine are synthesized in axonal terminals • Epinephrine is released by the adrenal medulla as a hormone Figure 11.22

24. BIOGENIC AMINES Norepinephrine (aka Noradrenaline) Main NT of the sympathetic branch of autonomic nervous system Binds to adrenergic receptors ( or  -many subtypes, 1, 2, etc) Excitatory or inhibitory depending on receptor type bound “Feeling good” NT Release enhanced by amphetamines Removal from synapse blocked by antidepressants and cocaine Dopamine Binds to dopaminergic receptors of substantia nigra of midbrain and hypothalamus “Feeling good” NT Release enhanced by amphetamines Reuptake block by cocaine Deficient in Parkinson’s disease May be involved in pathogenesis of schizophrenia

25. Serotonin (5-HT) The synthesis of serotonin involve two reactions: 1) Hydroxylation: Tryptophan 5- Hydroxytryptophan The enzyme catalyzes this reaction is Tryptophan Hydroxylase. The Co- factor is Tetrahydrobiopterin, which converted in this reaction to Dihydrobiopterin Synthesized from a.a. tryptophan

26. 2) Decarboxylation: 5- hydroxytryptophan Serotonin The enzyme is hydroxytryptophan decarboxylase. Serotonin is synthesized in CNS, & Chromaffin cells.

27. Monoamine oxidase Break down of serotonin: • Serotonin is degraded in two recations • 1) Oxidation: • 5-hydroxytryptoamine + O2 + H2O • 5- Hydroxyinodole-3- • acetaldehyde • 2) Dehydrogenation • 5- Hydroxyinodole-3-acetaldehyde 5-hydroxindole-3-acetate(Anion of 5-hydroxyindoleacetic acid) Aldehyde dehydrogenase

28. May play a role in sleep, appetite, and • regulation of moods • Drugs that block its uptake relieve • anxiety and depression • SSRI’s = selective serotonin reuptake • inhibitors • Include drugs such as Prozac, • Celexa, Lexapro, Zoloft

29. Neurotransmitters: Amino Acids • Include: • GABA – Gamma ()-aminobutyric acid • Glycine • Aspartate • Glutamate • Found only in the CNS

30. Amino Acids • GABA • Main inhibitory neurotransmitter in the brain • Inhibitory effects augmented by alcohol and antianxiety drugs like Valium • Increases influx of Cl- in postsynaptic neuron, • hyperpolarising it and thus inhibiting it! • GLUTAMATE • * Widespread in brain where it represents the major • excitatory neurotransmitter • Important in learning and memory • “Stroke NT” -excessive release produces excitotoxicity: • neurons literally stimulated to death; most commonly • caused by ischemia due to stroke (Ouch!) • Aids tumor advance when released by gliomas (ouch!)

31. SYNTHESIS AND RELEASE OF GLUTAMATE

33. NMDA RECEPTOR

34. FUNCTIONS OF GLUTAMATE 1. Glutamate acts as the major excitatory transmitter in the brain 2. Excess glutamate causes neuronal damage and death, principally by elevating cellular Ca+2. This phenomenon has significance for a number of pathologies such as Alzheimer’s disease, ALS, Ischemia and Hypoxia, Epilepsy and Schizophrenia. 3. Glutamate receptors are involved in a physiological phenomenon called long-term potentiation (LTP) - a cellular model of learning and memory. The NMDA receptor activation is an absolute requirement for LTP induction, however, AMPA and metabotropic glutamate receptors also play important roles.

35. SYNTHESIS AND RELEASE OF GABA

36. GABA Gambar 46. Metabolisme γ amino butirat Catatan: PLP = piridoksal fosfat.

37. GABAA RECEPTOR

38. FUNCTIONS OF GABA • GABA acts as the major inhibitory transmitter • in the brain 2. GABA has been implicated in several neurological and psychiatricdisorders of humans including Huntington’s chorea, epilepsy, alcoholism, Parkinson’s disease and anxiety disorders. 3. Antiepileptic and anxiolytic properties of benzodiazepine and phenobarbital suggest an important role of GABA in epilepsy as well as anxiety disorders.

39. Neurotransmitters: Peptides • Include: • Substance P – mediator of pain signals • Beta endorphin, dynorphin, and enkephalins • Act as natural opiates, reducing our perception of pain • Found in higher concentrations in marathoners and women who have just delivered • Bind to the same receptors as opiates and morphine

40. Neurotransmitters: Novel Messengers • Nitric oxide (NO) • A short-lived toxic gas; diffuses through post-synaptic membrane to bind with intracellular receptor (guanynyl cyclase) • Is involved in learning and memory • Some types of male impotence treated by stimulating NO release (Viagra) • Viagra  NO release  cGMP  smooth muscle relaxation  increased blood flow  erection • Can’t be taken when other pills to dilate coronary b.v. taken • Carbon monoxide (CO) is a main regulator of cGMP in the brain

41. Neurotransmitter Molecule Derived From Site of Synthesis Acetylcholine Choline CNS, parasympathetic nerves Serotonin5-Hydroxytryptamine (5-HT) Tryptophan CNS, chromaffin cells of the gut, enteric cells GABA Glutamate CNS Histamine Histidine hypothalamus Epinephrine synthesis pathway Tyrosine adrenal medulla, some CNS cells Norpinephrine synthesis pathway Tyrosine CNS, sympathetic nerves Dopamine synthesis pathway Tyrosine CNS Nitric oxide, NO Arginine CNS, gastrointestinal tract Summary: