Download Synthesis and degradation of neurotransmitters

Synthesis and degradation
of neurotransmitters
Josef Fontana
Overview of the lecture
• Definition of neurotransmitter and neuromodulator
• Metabolism of neurotransmitters and neuromodulators
(synthesis, postsynaptic receptor (receptors), the
mechanism of removal from the synaptic cleft, the
importance for clinical practice and pharmacology)
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a) Amino acids
excitatory: glutamate, aspartate
inhibitory: GABA, glycine
b) Monoamines
Catecholamines: NA, dopamine
Serotonin (melatonin)
c) Acetylcholine
d) Peptides
e) Other: purines, gases, endogenous cannabinoids
Definition of neurotransmitter
and neuromodulator
Neurotransmiter neuromodulátor
• 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
Metabolism of neurotransmitters
and neuromodulators
a) Amino acids
excitatory: glutamate,
aspartate
Glutamate
• Most common excitatory
neurotransmitter (40% of all
synapses)
• Synthesis:
– 2-KG from Krebs cycle (GDH or
transaminase)
– Deamination of glutamine (glutaminase)
Glutamate
• Postsynaptic receptors:
– NMDA (N-methyl-D-aspartate) –
belongs to ionotropic receptors,
requires the binding of the coagonists (glycine and D-serine) for the
efficient opening of the ion channel
– AMPA (α-amino-3-hydroxy-5- methyl4-isoxazolepropionate)
– Cainate
D-serine
D-cykloserine
Glycine
Glutamate
NR1
NR2
Ca+
Glutamate - Clinical significance
• NMDA antagonists: ketamine
(dissociative anesthesia),
phencyclidine ("angel dust")
• excitotoxity: excesive glutamate
release (epilepsy, traumatic brain
injury), leads to Na+ and Ca2+ IC
accumulation - swelling
• controlling synaptic plasticity and
memory function
Aspartate
• Excitatory neurotransmitter, mostly in
spinal cord
• Synthesis:
– derived from OAA (Krebs cycle)
–
• Postsynaptic receptor:
– NMDA – lower affinity than glutamate
–
• Removal from synaptic cleft: re-uptake
Metabolism of neurotransmitters
and neuromodulators
a) Amino acids
inhibitory: GABA, glycine
GABA = γ-aminobutyric acid
• The most important inhibitory
neurotransmitter of the brain
• Synthesis: GABA shunt
GABA - postsynaptic receptors
• GABAA: chloride channel
• agonists: benzodiazepines, barbiturates
• antagonists: flumazenil
• GABAB: metabotropic receptor
→ G-prot → opening of K+ channels
• agonist: baclofen
Glycine
• Inhibitory neurotransmitter of spinal
cord
• Synthesis:
– from serine
–
• Postsynaptic receptor:
– chloride channel: IPSP
– (co-agonist on NMDA receptors)
– Antagonist = strychnine -„seizure poison“
Metabolism of neurotransmitters
and neuromodulators
b) Monoamines
Catecholamines: NA, dopamine
Catecholamines are
made from tyrosine
• The conversion of tyrosine to
epinephrine requires four
sequential steps:
• 1) ring hydroxylation
• 2) decarboxylation
• 3) side chain hydroxylation to
form norepinephrine
• 4) N-methylation to form
epinephrine
Catecholamines are made from
tyrosine
• Tyrosine hydroxylase is rate-limiting
step for catecholamine synthesis.
• It converts L-tyrosine to Ldihydroxyphenylalanine (L-dopa).
• As the rate-limiting enzyme, tyrosine
hydroxylase is regulated in a variety of ways.
• The most important mechanism involves
feedback inhibition by the catecholamines.
Catecholamines are made from
tyrosine
• Dopa decarboxylase is present in all
tissues.
• This enzyme transforms L-dopa to 3,4dihydroxyphenylethylamine (dopamine).
• Compounds that resemble L-dopa, such as αmethyldopa, are competitive inhibitors of this
reaction – α-methyldopa is effective in
treating some kinds of hypertension.
Catecholamines are made from
tyrosine
• Dopamine-β-hydroxylase catalyzes the
conversion of dopamine to
norepinephrine.
Catecholamines are made from
tyrosine
• Phenylethanolamine-Nmethyltransferase (PNMT) catalyzes
the production of epinephrine.
• PNMT catalyzes the N-methylation of
norepinephrine to form epinephrine in the
adrenal medulla.
Catecholamin synthesis
Tyrosine
hydroxylase
H
C C COOH2
NH3+
1.
Phenylalanin
H
C C COOH2
NH3+
HO
2.
HO
Tyrosin
3,4 DihydrOxyPhenylAlanin (DOPA)
DOPA decarboxylase
H H2
C C
HO
HO
Adrenalin
H H2
C C
5.
HO
OH NH
CH3
HO
N-methyltransferase
H
C C COOH2
NH3+
HO
OH NH3+
4.
3.
HO
HO
Dopamine βhydroxylase
Noradrenalin
Dopamin
H2
C C + CO2
H2
NH3+
Catecholamines are made from
tyrosine
• Catecholamines cannot cross the blood-brain
barrier – in the brain they must be
synthesized locally.
• In certain central nervous system diseases
(eg. Parkinson's disease), there is a local
deficiency of dopamine synthesis.
• L-Dopa, the precursor of dopamine, readily
crosses the blood-brain barrier and so is an
important agent in the treatment of
Parkinson's disease.
Catecholamine breakdown
Reuptake followed by IC degradation:
COMT = catechol-o-methyl transferase
MAO = monoaminooxidase
MAO
HO
H
C
77
COO78
OH
CH3O
COMT
Inhibitors of MAO (IMAO)
= antidepresive drugs
Final metabolite: vanilmandelic acid
Noradrenalin
• Postsynaptic receptors:
• metabotropic: α1, β1 …
• there are also presynaptic receptors: α2
– inhibit NA release from neuron
• Adrenergic systems:
• locus coeruleus, lateral tegmentum
• arousal, stress, mood
Dopamine
• Postsynaptic receptors are metabotropic:
• D1: Gs-protein → cAMP → modulation of ion.
channels → EPSP
• D2: Gi-protein: phosphodiesterase activation →
IPSP
System
Anatomy
Function
Significance
Mesocortical
tegmentum→fron
t. cortex
Motivation, mood, Schizophreny
will
Mesolimbic
tegmentum→ nc.
accumbens
dtto
Schizophreny,
addiction
Nigrostriatal
s.nigra→striatum
Motoric system
M.Parkinson
Tuberoinfundibul
ar
Inhibits prolactin
nc. arcuatus→
eminent. mediana secretion
Adverse eff. of
antipsychotics
Dopaminergic systems
Nigrostriatal
Mesolimbic
Mesocortical
Tuberoinfundibular
Dopamine – Clinical significance
• Antipsychotics:
• phenothiazines = D-receptor blockers
• AE = parkinsonism, hyperprolactinemia
• Cocaine, amphetamines:
• dopamine and NA re-uptake blockers
• Parkinson disease: loss of dopaminergic
neurons in s. nigra. Treatment: L-DOPA
Metabolism of neurotransmitters
and neuromodulators
b) Monoamines
Serotonin (melatonin)
Serotonin
• = 5-hydroxytryptamin
• Anatomy: limbic system, reticular
formation
• Function:
– anger/aggression, mood, sleep
– appetite/satiety/vomitting
– body temperature
– sexual behavior
Degradation by MAO: 5-hydroxyindolacetate
Melatonin
• Pineal gland
• Biorythms
• Hormone/neuromodulator
Metabolism of neurotransmitters
and neuromodulators
c) 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:
CH
H3C
C
O
O
+
3
C C N CH3
H2 H2 CH
3
• degradation: Acetylcholine eserase
Acetylcholine - postsynaptic
receptors
• Nicotinic = inotropic - Na+ channels
• NM (muscular) - on the neuromuscular
junction
• NN receptor (neuronal type) –
postsynaptic membranes in autonomic
ganglia and brain
Acetylcholin - postsynaptické
receptory
• Muscarinic = metabotropic
• M1 = Gq-prot.: ↓K+ current: CNS
(cognitive function), autonomic ganglia
• M2 = Gi-prot.: ↑K+ current: CNS, heart
• M3 = Gq-prot.: eye, glands
• M4 and M5: CNS, eye
M1, M3, M5 receptors
muscarinic
receptor
M2, M4 receptors
muscarinic
receptor
Acetylcholine – Clinical significance
• Lecithin = phosphatidylcholine
(acetylcholine precursor)
• Acetylcholine esterase inhibitors:
• physostigmine (passes through HEB): arousal
from general anesthesia
• donepezil, rivastigmine and galantamine (pass
through HEB): Alzheimer's disease therapy
• neostigmine (does not pass): psympatomimetic, myastenia gravis
Irreversible inhibitors of ACHE
- organophosphates
• products used in agriculture (herbicides,
pesticides, BC)
• chemical warfare agents: tabun, sarin,
soman (good penetration through the
skin and mucous membranes)
• symptoms of poisoning: nausea,
vomiting, headache, weakness, sweating,
salivation, bradycardia, muscle spasms,
breathing difficulty or arrest
Acetylcholine – Clinical significance
• M-receptor blockade = atropin
(parasympatolytics)
• N-receptor blockade = curare
(arrow poison) - derivatives =
muscle relaxants
Metabolism of neurotransmitters
and neuromodulators
d) Peptides
Peptides
• Appr. 50 known
• Mainly in the hypothalamic-pituitary
system
• Synthesis: prepropeptid → ER, signal
sequence cleavage → propeptid 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, inhibit l. coeruleus
• axo-axonal synapse
• NP-Y
• mediates the influence of leptin on food
intake
• Neurotensine:
• regulates LH and prolactin secretion
• Substance P…
Metabolism of neurotransmitters
and neuromodulators
e) Other: purines, gases,
endogenous cannabinoids
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
• CB1 – in CNS – regulates cognitive
function, food intake
• CB2 – periphery - the immune system