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, neuromodulator
Synapsis
Excitatory 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
Amino acid
• excitatory: Glu, Asp
• inhibitory: GABA, Gly
Monoamines
• Catecholamines: NA, D
• Serotonin, (melatonin)
Acetylcholine
Peptides
Others
• NPY, ADH, neurotensin …
• purines, gases, endogenous
cannabinoids
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-hydroxy5-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
Amino acid
• excitatory: Glu, Asp
• inhibitory: GABA, Gly
Monoamines
• Catecholamines: NA, D
• Serotonin, (melatonin)
Acetylcholine
Peptides
Others
• NPY, ADH, neurotensin …
• purines, gases, endogenous
cannabinoids
Catecholamines: Synthesis
C
H2
1.
H
C
H
C C COOH2
NH3+
HO
COO-
NH3+
Phenylalanin
Tyrosin
2.
H
C C COOH2
NH3+
HO
HO
3,4 DihydrOxyPhenylAlanin (DOPA)
3.
H
C
HO
H2
C
5.
H
C
HO
OH NH
HO
Adrenalin
CH3
HO
H2
C
OH NH3+
Noradrenalin
4.
C
H2
HO
HO
Dopamin
H2
C
+
NH3+
CO2
Catecholamines - Degradation
• Reuptake followed by IC degradation:
MAO
H
C COOHO
77
78
OH
CH3O
COMT
• Final metabolite: vanilmandelic acid
Dopamine
• Receptors are metabotropic:
▫ D1: Gs proteincAMP ion. channel phosph.
EPSP
▫ D2: Gi protein: phosphodiesterase activation
IPSP
Dopaminergic systems
System
Anatomy
Function
Significance
Mesocortical
tegmentumfron
t. cortex
Motivation,
mood, will
Schizophreny
Mesolimbic
tegmentum nc.
accumbens
dtto
Schizophreny,
addiction
Nigrostriatal
s.nigrastriatum
Motoric system
M.Parkinson
Tuberoinfundibul
ar
Inhibits prolactin
nc. arcuatus
eminent. mediana 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
Amino acid
• excitatory: Glu, Asp
• inhibitory: GABA, Gly
Monoamines
• Catecholamines: NA, D
• Serotonin, (melatonin)
Acetylcholine
Peptides
Others
• NPY, ADH, neurotensin …
• purines, gases, endogenous
cannabinoids
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: CH3
+
H3C C O C C N CH3
H2 H2 CH
3
O
• Degradation: Acetylcholine eserase
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
Amino acid
• excitatory: Glu, Asp
• inhibitory: GABA, Gly
Monoamines
• Catecholamines: NA, D
• Serotonin, (melatonin)
Acetylcholine
Peptides
Others
• NPY, ADH, neurotensin …
• purines, gases, endogenous
cannabinoids
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
Amino acid
• excitatory: Glu, Asp
• inhibitory: GABA, Gly
Monoamines
• Catecholamines: NA, D
• Serotonin, (melatonin)
Acetylcholine
Peptides
Others
• NPY, ADH, neurotensin …
• purines, gases, endogenous
cannabinoids
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…
0
