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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

Neurotransmitters

František Duška

overview
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
1 general physiology of synaptic transmission
1. General physiology of synaptic transmission

Definice: neurotransmitter, neuromodulator

Synapsis

Excitatory and inhibitory postsynaptic potentials

definitions of terms
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
postsynaptic membrane
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
summatin of postsynaptic potentials
Summatin of postsynaptic potentials
  • Neurone: integrates inputs (EPSPs, IPSPs) into output: 0 or 1 (action potential or not)
2 neurotransmitter metabolism
2. Neurotransmitter metabolism

synthesis

postsynaptic receptor (receptors)

mechanism of removal from synaptic cleft

clinical and pharmacological significance

glutamate
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
glutamate12
Glutamate
  • Clinical significance:
    • antagonisté NMDA: ketamin (disociativní anestezie), fencyklidin („angel dust“)
    • excitotoxicita
    • synaptická plasticita, role v učení and paměti
aspartate
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
gaba aminobutyric acid
GABA = γ-aminobutyric acid
  • inhibitory neurotransmitter of the brain Synthesis: GABA shunt
gaba postsynaptic receptors
GABA: postsynaptic receptors
  • GABAA: chloridový channel
    • agonisté: benzodiazepiny, barbituráty
    • antagonisté: flumazenil
  • GABAB: metabotropní rec.G-prototevření K+ channel
    • agonista: baclofen
glycine
Glycine
  • Inhibitory neurotransmitter of spinal cord
  • Synthesis:
    • from serine
  • Receptor
    • chloride channel: IPSP
    • (co-agonist on NMDA receptors)
  • Antagonist = strychnine
    • „seizure poison“
catecholamines degradation
Catecholamines - Degradation
  • Reuptake followed by IC degradation:
  • Final metabolite: vanilmandelic acid
dopamine
Dopamine
  • Receptors are metabotropic:
    • D1: Gs proteincAMP ion. channel phosph. EPSP
    • D2: Gi protein: phosphodiesterase activation IPSP
dopamine clinical significance
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

noradrenaline
Noradrenaline
  • postsynaptic receptors:
    • metabotropic: α1, 1 …
    • ! presynaptic, inhibitory receptors also exist: α2
  • Adrenergic systems:
    • locus coeruleus, lateral tegmentum
    • arousal, stress, mood
serotonin
Serotonin
  • = 5-hydroxytryptamin
  • Anatomy: limbic systém, retikular formation
  • Function:
    • anger/aggression, mood, sleep
    • appetite/satiety/vomitting
    • body temperature
    • sexual behavior
serotonin27
Serotonin
  • Degradation MAO: 5-hydroxyindolacetate
melatonine
Melatonine
  • Pineal gland
  • Biorythms
  • Hormone/neuromodulator
acetylcholine
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
acetylcholine postsyn receptors
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.
acetylcholine clinical significance
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)
peptides
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
peptides examples
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…
others
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
closing remark
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…