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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▫Others: purines, gases, endogenous cannabinoids
Definice: neurotransmitter, neuromodulatorSynapsisExcitatory and inhibitory postsynaptic potentials
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•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
•Neurone: integrates inputs (EPSPs, IPSPs) into output: 0 or 1 (action potential or not)
Summatin of postsynaptic potentials
-synthesis-postsynaptic receptor (receptors)-mechanism of removal from synaptic cleft -clinical and pharmacological significance
Chemical groups of neurotransmitters
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
Glutamate
•Clinical significance:▫antagonisté NMDA: ketamin (disociativní
anestezie), fencyklidin („angel dust“)▫excitotoxicita▫synaptická plasticita, role v učení and
paměti
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 = γ-aminobutyric acid
•inhibitory neurotransmitter of the brain Synthesis: GABA shunt
GABA: postsynaptic receptors
•GABAA: chloridový channel▫agonisté: benzodiazepiny, barbituráty▫antagonisté: flumazenil
•GABAB: metabotropní rec.G-prototevření K+ channel▫agonista: baclofen
Glycine
•Inhibitory neurotransmitter of spinal cord•Synthesis:
▫from serine•Receptor
▫chloride channel: IPSP▫(co-agonist on NMDA receptors)
•Antagonist = strychnine▫„seizure poison“
Chemical groups of neurotransmitters
Catecholamines: Synthesis
CH2
CH
NH3+
COO- CH2
CH
NH3+
COO-OH CH2
CH
NH3+
OH
OH
COO-
CH2
CH
2
NH3+
OH
OH
CO2CH
CH
2
NH3+
OH
OHOH
CH
CH
2
NH
OH
OHOH
CH3
Phenylalanin Tyrosin 3,4 DihydrOxyPhenylAlanin (DOPA)
+
Adrenalin Noradrenalin Dopamin
1. 2.
3.
4.5.
Catecholamines - Degradation
•Reuptake followed by IC degradation:
•Final metabolite: vanilmandelic acid
CH
77COO-78
OH
CH3OOH
COMT
MAO
Dopamine
•Receptors are metabotropic:▫D1: Gs proteincAMP ion. channel
phosph. EPSP▫D2: Gi protein: phosphodiesterase
activation IPSP
Dopaminergic systems
System Anatomy Function Significance
Mesocortical tegmentumfront. cortex
Motivation, mood, will
Schizophreny
Mesolimbic tegmentum nc. accumbens
dtto Schizophreny, addiction
Nigrostriatal s.nigrastriatum
Motoric system M.Parkinson
Tuberoinfundibular
nc. arcuatus eminent. mediana
Inhibits prolactin secretion
Adverse eff. of antipsychotics
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
•postsynaptic receptors:▫metabotropic: α1, 1 …▫! presynaptic, inhibitory receptors also
exist: α2 •Adrenergic systems:
▫locus coeruleus, lateral tegmentum▫arousal, stress, mood
Serotonin
•= 5-hydroxytryptamin•Anatomy: limbic systém, retikular
formation•Function:
▫anger/aggression, mood, sleep▫appetite/satiety/vomitting▫body temperature▫sexual behavior
Serotonin
•Degradation MAO: 5-hydroxyindolacetate
Melatonine
•Pineal gland•Biorythms•Hormone/neuromodulator
Chemical groups of neurotransmitters
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
CH2
CH2
O N+
CH3
CH3CH3
CCH3
O
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•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)
Chemical groups of neurotransmitters
Peptides
•Appr. 50 known•Hypothalamus•Synthesis:
▫prepropeptidER, signal sequence cleavage propeptide in vesicles further processing peptide neurotransmitter (1 or more)
•Removal from synaptic cleft:▫Degradation, but not re-uptake
Peptides:
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…
Chemical groups of neurotransmitters
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
•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…