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Neurotransmitters

Neurotransmitters. František Duška. Overview. General physiology of synaptic transmission Chemical division of neurotransmitters Amino acid excitatory: Glu, Asp inhibitory: GABA, Gly Monoamines: Catecholamines: NA, D Serotonin, (melatonin) Acetylcholine Peptides

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Neurotransmitters

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  1. Neurotransmitters František Duška

  2. Overview • General physiology of synaptic transmission • Chemical division of neurotransmitters • Amino acid • excitatory: Glu, Asp • inhibitory: GABA, Gly • Monoamines: • Catecholamines: NA, D • Serotonin, (melatonin) • Acetylcholine • Peptides • Others: purines, gases, endogenous cannabinoids

  3. 1. General physiology of synaptic transmission Definice: neurotransmitter, neuromodulator Synapsis Excitatory and inhibitory postsynaptic potentials

  4. Definitions of terms • neurotransmitter: • a componud secreted into synaptic cleft and bound to postsynaptic receptors • removal from synaptic cleft by spercific biochemical mechanism • neuromodulator: • a compound secreted by neurons into environment and spread by diffusion (or CSF) • modulates behavior of other neurons

  5. Postsynaptic membrane • Resting ponential = - 70 mV • negative IC, positive EC • spontaneous depolarization treshold = -55 mV • Excitatory neurotransmitters  EPSP: • open Ca2+, Na+ channels (influx) • depolarize = decrease membrane negativity • Inhibitory neurotransmitters  IPSP • open K+ channels (efflux) or Cl- channels (influx) • hyperpolarize = increase negativity

  6. Summatin of postsynaptic potentials • Neurone: integrates inputs (EPSPs, IPSPs) into output: 0 or 1 (action potential or not)

  7. Summatin of postsynaptic potentials

  8. 2. Neurotransmitter metabolism synthesis postsynaptic receptor (receptors) mechanism of removal from synaptic cleft clinical and pharmacological significance

  9. Chemical groups of neurotransmitters

  10. Glutamate • Most cammon excitatory neurotransmitter • Synthesis: • from 2-OG (GDH or transaminase) • deamination of glutamine (glutaminase) • postsynaptic receptors: • NMDA (N-methyl-D-aspartát): • AMPA (α-amino-3-hydroxy- 5-methyl-4-isoxazolepropionate) • cainate

  11. Glutamate • Clinical significance: • antagonisté NMDA: ketamin (disociativní anestezie), fencyklidin („angel dust“) • excitotoxicita • synaptická plasticita, role v učení and paměti

  12. Aspartate • Excitatory neurotransmitter, mostly of spinal cord • Synthesis • derived from OAA (citric acid cycle) • Postsynaptic receptor • NMDA – lower affinity than Glu • Removal from synaptic cleft: re-uptake

  13. GABA = γ-aminobutyric acid • inhibitory neurotransmitter of the brain Synthesis: GABA shunt

  14. GABA: postsynaptic receptors • GABAA: chloridový channel • agonisté: benzodiazepiny, barbituráty • antagonisté: flumazenil • GABAB: metabotropní rec.G-prototevření K+ channel • agonista: baclofen

  15. Glycine • Inhibitory neurotransmitter of spinal cord • Synthesis: • from serine • Receptor • chloride channel: IPSP • (co-agonist on NMDA receptors) • Antagonist = strychnine • „seizure poison“

  16. Chemical groups of neurotransmitters

  17. Catecholamines: Synthesis

  18. Catecholamines - Degradation • Reuptake followed by IC degradation: • Final metabolite: vanilmandelic acid

  19. Dopamine • Receptors are metabotropic: • D1: Gs proteincAMP ion. channel phosph. EPSP • D2: Gi protein: phosphodiesterase activation IPSP

  20. Dopaminergic systems

  21. Dopamine – Clinical significance • Antipsychotics: • phenothiazines = D-receptor blockers • AE = parkinsonism, hyperprolactinemia • Cocaine, amfetamines: • dopamine re-uptake blockers • Parkinson disease: • loss of dopaminergic neurons in s. nigra. Treatment: L-DOPA

  22. Noradrenaline • postsynaptic receptors: • metabotropic: α1, 1 … • ! presynaptic, inhibitory receptors also exist: α2 • Adrenergic systems: • locus coeruleus, lateral tegmentum • arousal, stress, mood

  23. Serotonin • = 5-hydroxytryptamin • Anatomy: limbic systém, retikular formation • Function: • anger/aggression, mood, sleep • appetite/satiety/vomitting • body temperature • sexual behavior

  24. Serotonin • Degradation MAO: 5-hydroxyindolacetate

  25. Melatonine • Pineal gland • Biorythms • Hormone/neuromodulator

  26. Chemical groups of neurotransmitters

  27. Acetylcholine • CNS: pontomesencefalotegmental complex • autonomic NS: preganglionic mediator of both symp. and p-symp., postganglionic mediator of p-symp • peripheral NS: neuromuscular junction • Synthesis: AcCoA + choline: • Degradation: Acetylcholine eserase

  28. Acetylcholine: postsyn. receptors • Nicotinic = inotropic • Na+ channels, neuromuscular junction • Muscarinic = metabotropic • M1 = Gq-prot. = K+ current: CNS (cognit. function), autonomic ganglia • M2= Gi-prot = K+current: CNS, heart • M3= Gq: eye, glands • etc.

  29. Acetylcholine –Clinical significance • Lecithin = phosphatidylcholine as nootropic agent • Acetylcholine esterase inhibitors: • physostigmine (passes through HEB): arousal from general anesthesia • neostigmine (does not pass): p-sympatomimetic, myastenia gravis • M-receptor blockade = atropin • parasympatolytics • N-receptor blockade = curare (arrow poison)

  30. Chemical groups of neurotransmitters

  31. Peptides • Appr. 50 known • Hypothalamus • Synthesis: • prepropeptidER, signal sequence cleavage  propeptide in vesicles  further processing  peptide neurotransmitter (1 or more) • Removal from synaptic cleft: • Degradation, but not re-uptake

  32. Peptides:

  33. Peptides: examples • Opioids: endorfines, enkefalins • limbic system, inhibits l. coeruleus • axo-axonal synapsis • NP-Y • mediates the influence of leptin on food intake • Neurotensine: • regulates LH and prolactin secretion • substance P…

  34. Chemical groups of neurotransmitters

  35. Others • Endocannabinoid system: • retrograde neurotransmission: anandamide • synthesized in the postsynaptic neurone • diffuses to presynaptic neurone • bound to CB1 and CB2 rec. (G-prot.) • influence presynaptic neuron behavior • regulates cognitive function, food intake • THC as illicit drug

  36. Closing remark • Neurotransmitters cannot cross hematoencefalic barrier • Chemically identical compounds have many functions aoutside the brain. • These have not been discussed!! • catecholamines in regulating blood pressure and blood flow • serotonin: immunity • pituitary peptides…. etc…

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