Nerve cells
Neurotransmission across synapsesNeurotransmission across synapses
Biochemistry II
Lecture 7 2008 (J.S.)
DendritesNeurons
Perikaryon – the metabolic centre of neuron,
with intensive proteosynthesis, is highly
Dendrites
with receptors of neurotransmitters.
Neurons
with intensive proteosynthesis, is highly
susceptible to low supply of oxygen.
AxonAxon
– the primary active transport of Na+ and K+ ions across
axolemma and voltage operated ion channels enables
inception and spreading of action potentials.inception and spreading of action potentials.
– axonal transport (both anterograde and
retrograde) provides shifts of proteins, mitochondria,
and synaptic vesicles between perikaryon and
Myelin sheaths are wrapped about most axons,
and synaptic vesicles between perikaryon and
synaptic terminals.
Myelin sheaths are wrapped about most axons,
segmentation of sheaths by nodes of Ranvier enables
the rapid saltatory conduction of nerve impulses.
Axon terminals - synapses
– neurotransmitters are released from synaptic vesicles
into the synaptic cleft by exocytosis.
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into the synaptic cleft by exocytosis.
GlucoseGlucose
is the main nutrient for the nervous system. If glucose is lacking
(prolonged starvation), utilization of ketone bodies can meet up to one
half of requirements for energy.half of requirements for energy.
In CNS, the transport of glucose through capillary walls is much less
efficient, when compared with other tissues. Thus impairments of
consciousness are usually the first clinical symptoms of hypoglycaemia.
efficient, when compared with other tissues. Thus impairments of
consciousness are usually the first clinical symptoms of hypoglycaemia.
Walls of blood capillaries in peripheral tissues - in in the brainWalls of blood capillaries in peripheral tissues - in in the brain
GlcGlc
spinal fluidinterstitial fluid spinal fluid
– free diffusion through intercellular space
– pinocytosis (transcytosis)
– numerous tight junctions limit free diffusion
– no pinocytosis
interstitial fluid
– pinocytosis (transcytosis)
– glucose transporters
– no pinocytosis
– the basement membrane is highly consistent
– transporters GLUT3 have low efficiency
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Axonal transportAxonal transport
In the axon, there is a fast axonal transport along microtubules. It works
Kinesin drifts proteins, synaptic vesicles, and mitochondria in
In the axon, there is a fast axonal transport along microtubules. It works
on the principle of a molecular motor, via the motile proteins.
Kinesin drifts proteins, synaptic vesicles, and mitochondria in
anterograde transport, dynein in retrograde transport.
anterograde transport
retrograde transport
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Myelin sheaths are formed by wrapping ofMyelin Myelin sheaths are formed by wrapping of
protruding parts of glial cells round the
axons; oligodendrocytes produce myelin
sheaths in CNS, the Schwann cells in the
Myelin
sheaths in CNS, the Schwann cells in the
peripheral part of the nervous system.
Numerous plasma membranes are tightlyNumerous plasma membranes are tightly
packed so that the original intracellular and
extracellular spaces cannot beextracellular spaces cannot be
differentiated easily.
Myelin membranes contain about 80 % lipids.
The main proteins are
cytoplasmic sides
The main proteins are
- proteolipidic protein,
- the basic protein of myelin (encephalitogen),
the "outer“ sides
- high molecular-weight protein
called Wolfram's protein.
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Nerve impulse
Neurons are irritable cells that react, after an adequate stimulation, by
formation of nerve impulses – action potentials caused by changes in ion
flows across cell membranes. Action potential spread without decreasingflows across cell membranes. Action potential spread without decreasing
along axons to the axon terminals.
The lipidic dilayer is practically impermeable to the unevenly distributedThe lipidic dilayer is practically impermeable to the unevenly distributed
Na+ and K+ ions. The resting membrane potential –70 mV on the inner
side of the plasma membrane.side of the plasma membrane.
Sodium and potassium ion channels allow the passive passage across the
membrane:
– leakage (voltage-independent) K+ channels,– leakage (voltage-independent) K+ channels,
– ligand-gated Na+/K+ channel,
– voltage-operated Na+ channel, and– voltage-operated Na channel, and
– voltage-operated K+ channel.
The inward flow of Na+ is the cause of depolarization (spike potential),The inward flow of Na is the cause of depolarization (spike potential),
the following outward flow of K+ repolarization and the refractory phase.
The original uneven distribution of ions is restored by
– Na+,K+–ATPase.
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– Na+,K+–ATPase.
Neurosecretion
Stimulated neurons release neurotransmitters by exocytosis ofStimulated neurons release neurotransmitters by exocytosis of
synaptic vesicles (synaptosomes) into the synaptic clefts.
In the central nervous system, specific neuron types releaseIn the central nervous system, specific neuron types release
neurohormones or other neuropeptides, which may have special
regulatory functions (co-transmitters, neuromodulators).regulatory functions (co-transmitters, neuromodulators).
liberins
or statinsacetylcholine or statins
acetylcholine
acetylcholine
acetylcholine
vasopressin (ADH)
and oxytocinadrenaline
acetylcholine
noradrenaline and oxytocinadrenalinenoradrenaline
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Synaptic transmission
Neurotransmitters act as chemical signals between nerve cells
or between nerve cells and the target cells.or between nerve cells and the target cells.
voltage-gated Ca2+ channel
depolarization wave
receptor
synaptic vesicles
depolarization wave
Ca2+
postsynaptic
membrane
synaptic vesicles
(synaptosomes)
synaptic cleft
membrane
The response to the neurotransmitter depends on the receptor type:
– ionotropic receptors (ion channels) evoke a change in the
membrane potential - an electrical signal,membrane potential - an electrical signal,
– metabotropic receptors are coupled to second messenger
pathway, the evoked signal is a chemical one.
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pathway, the evoked signal is a chemical one.
Neurotransmitters
A large number (much more than 30) of neurotransmitters have beenA large number (much more than 30) of neurotransmitters have been
described. Many of them are derived from simple compounds, such as
amino acids and biogenic amines, but some peptides are also known toamino acids and biogenic amines, but some peptides are also known to
be important neurotransmitters. The principal transporters:
Central nervous system
Peripheral neurons
– efferent
inhibitory GABA (at least 50 %)
glycine (spinal cord)
excitatory glutamate (more than 10 %) – efferent
excitatory acetylcholine
noradrenaline
excitatory glutamate (more than 10 %)
acetylcholine (about10 %)
dopamine
(about 1 %, in the striatum 15 %)
– afferent sensory neurons
excitatory glutamate
(about 1 %, in the striatum 15 %)
serotonin
histamine
aspartate
excitatory glutamate
(Aβ fibres, tactile stimuli)
peptide substance P
(C and Aδ fibres, nociceptive)
aspartate
noradrenaline (less than 1 %,
but in the hypothalamus 5 %)
adenosine (C and Aδ fibres, nociceptive)adenosine
neuromodulatory endorphins, enkephalins,
endozepines, delta-sleep inducing peptide,
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endozepines, delta-sleep inducing peptide,
and possibly endopsychosins.
Neurotransmitter receptors
In contradistinction to numerous types of hormone receptors,
only two basal types of neurotransmitter receptors occur:
Neurotransmitter receptors
Ionotropic receptors – ligand-gated ion channels (ROC), e.g.
only two basal types of neurotransmitter receptors occur:
Ionotropic receptors – ligand-gated ion channels (ROC), e.g.
excitatory – acetylcholine nicotinic - Na+/K+ channel,
– glutamate (CNS, some afferent sensory neurons)– glutamate (CNS, some afferent sensory neurons)
- Na+/Ca2+/K+ channel,
inhibitory – GABAA receptor (brain) - Cl– channelinhibitory – GABAA receptor (brain) - Cl channel
Metabotropic receptors activating G proteins, e.g.
ββββGs protein – ββββ-adrenergic, GABAB receptor, dopamine D1,
Gi protein – αααα2-adrenergic, dopamine D3,
acetylcholine muscarinic M2 (opens also K+ channel),acetylcholine muscarinic M2 (opens also K+ channel),
Gq protein – acetylcholine muscarinic M1, αααα1-adrenergic.
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Ligand-gated ion channels (ROC, receptor-operated channels)
Acetylcholine nicotinic receptor – Na+/K+ channel, e.g., is the
asymmetric pentamer of four kinds of membrane-spanning homologous
subunits that is activated by binding of two molecules of acetylcholine.subunits that is activated by binding of two molecules of acetylcholine.
α2-subunits bind two
acetylcholine moleculesacetylcholine molecules
the closed state Na+
K+
αααα2 αααα2
a large inward
flow of Na+
synaptic
cleft
αααα2 αααα2
ββββ
flow of Na
a smaller outward
flow of K+
– –– –
changes in conformation, the channel
cytoplasm
binding sites for local anaesthetics,
undergoes frequent transitions between
open and closed states in few milliseconds
binding sites for local anaesthetics,
psychotropic phenothiazines. etc.
D-Tubocurarine is an antagonist of acetylcholine that prevents channel opening.
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Tubocurarine is an antagonist of acetylcholine that prevents channel opening.
Succinylcholine is a myorelaxant that produces muscular end plate depolarization.
Cholinergic synapse acetylcholine receptorsCholinergic synapse
depolarization wave Na+
acetylcholine receptors
ACETYLCHOLIN
Ca2+
choline acetyltransferase
(by axonal transport) ACETYLCHOLIN
membrane-bound
acetylcholinesterase
acetyl-CoA
ATP
(by axonal transport)
acetylcholinesterase
reuptake
choline
acetate
Increase in intracellular [Ca2+] activates Ca2+-calmodulin-dependent protein-Increase in intracellular [Ca2+] activates Ca2+-calmodulin-dependent proteinkinase
that phosphorylates synapsin-1; its interaction with the membrane of
synaptic vesicles initiates their fusion with the presynaptic membrane and
neurotransmitter exocytosis. The membranes of vesicles are recycled..neurotransmitter exocytosis. The membranes of vesicles are recycled..
At neuromuscular junctions, the arrival of a nerve impulse releases about 300 vesicles
(approx. 40 000 acetylcholine molecules in each), which raises the acetylcholine
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(approx. 40 000 acetylcholine molecules in each), which raises the acetylcholine
concentration in the cleft more than 10 000 times.
exist in two principal types that are named nicotinic and
Acetylcholine receptors
Nicotinic cholinergic receptors
exist in two principal types that are named nicotinic and
muscarinic after the two exogenous agonists.
Nicotinic cholinergic receptors
are acetylcholine-operated Na+/K+ channels (see picture 11);
in the peripheral nervous system, they occurin the peripheral nervous system, they occur
– in the dendrites of nearly all peripheral efferent neurons
(including adrenergic neurons), and
– at neuromuscular junctions ion the cytoplasmic– at neuromuscular junctions ion the cytoplasmic
membranes of skeletal muscles.
Muscarinic cholinergic receptors
Five types M exhibiting different functions are known.Five types M1–5 exhibiting different functions are known.
In the peripheral tissues innervated by the parasympathetic system,
receptors M predominate, the other types occur mostly in CNS.receptors M1 predominate, the other types occur mostly in CNS.
After acetylcholine has bound at muscarinic receptors M1, the
complex activates Gq proteins; the consequence - activation of thecomplex activates Gq proteins; the consequence - activation of the
phosphatidylinositol cascade: IP3 increases the intracellular Ca2+
concentration, proteinkinase C is activated by diacylglycerol.
13Atropin is an acetylcholine antagonist at muscarinic receptors.
Acetylcholine (cholinergic) receptors
of the peripheral efferent neuronsof the peripheral efferent neurons
NNNN
N
Most postganglionic
N
N Most postganglionic
neurons of the sympathetic
path are adrenergic
N
Adrenergic
receptorsN M1
motor neurons parasympathetic sympathetic
(neuromuscular junction) system system
receptors
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Adrenergic synapse
Neurotransmitter of most postganglionic sympathetic neuronsNeurotransmitter of most postganglionic sympathetic neurons
is noradrenaline.
depolarization wave
ββββ
Varicosities of the postganglionic sympathetic
axons are analogous to the nerve terminals.
DA ββββ-hydroxylase
synaptic vesicles
(axonal transport)
Ca2+
NORADRENALINE
presynaptic
adrenergic
receptors
mitochondrial
monoamine oxidasemonoamine oxidase
partial reuptake
adrenergic receptors in
membranes of the target cells
extracellular COMT
(catechol O-methyltransferase)
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of all types are receptors cooperating with G proteins.
Adrenergic receptors
of all types are receptors cooperating with G proteins.
ββββ-Adrenergic receptors
After binding an agonist, all types of β-receptors activate Gs proteins soAfter binding an agonist, all types of β-receptors activate Gs proteins so
that adenylate cyclase is stimulated, cAMP concentration increases,
and proteinkinase A is activated. Particular types differ namely in
their location and affinity to various catecholamines:their location and affinity to various catecholamines:
ββββ1 are present in the membranes of cardiomyocytes,
ββββ2 in the smooth muscles and blood vessels of the bronchial stem,ββββ2 in the smooth muscles and blood vessels of the bronchial stem,
ββββ3 in the adipose tissue.
αααα2-Adrenergic receptorsαααα2-Adrenergic receptors
The effect is quite opposite to that of β-receptors, binding of
catecholamines results in the interaction with Gi protein,catecholamines results in the interaction with Gi protein,
decrease in adenylate cyclase activity and in cAMP concentration.
αααα1-Adrenergic receptorsαααα1-Adrenergic receptors
activate Gq proteins and initiate the phosphatidylinositol cascade by
stimulation of phospholipase C resulting in an increase of
intracellular Ca2+ concentration and activation of proteinkinase C.
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intracellular Ca2+ concentration and activation of proteinkinase C.
Adrenergic receptors ββββ1, ββββ2, and ββββ3Adrenergic receptors ββββ1, ββββ2, and ββββ3
noradrenaline/adrenaline
AMP cyclaseββββ receptor
Gααααsβγβγβγβγ
Gααααsβγβγβγβγ
ATP
cAMP
AMP
cAMP
inactive
proteinkinase A
phosphodiesterases
H2O
AMP proteinkinase A
active proteinkinase Aphosphorylations active proteinkinase Aphosphorylations
The typical effects of β-stimulation:The typical effects of β-stimulation:
ββββ1 – tachycardia, inotropic effect in the myocard,
ββββ2 – bronchodilation, vasodilation in the bronchial tree,,
ββββ – mobilization of fat stores, thermogenesis.
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ββββ3 – mobilization of fat stores, thermogenesis.
Adrenergic receptors αααα2 a αααα1
Receptors αααα2 Receptors αααα1
adenylate cyclase phospholipase C
PL C
IP3 and diacylglycerol
Gi protein Gq protein
cAMP decrease
IP3 and diacylglycerol
increase in [Ca2+]
activation of PK Cactivation of PK C
The typical effects of adrenergic
αααα -stimulation: αααα -stimulation:αααα2-stimulation: αααα1-stimulation:
glandular secretion inhibited vasoconstriction
bronchoconstriction
motility of GIT inhibited
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motility of GIT inhibited
Inhibitory GABAA receptor
is a ligand-gated channel (ROC) for chloride anions. The interaction withis a ligand-gated channel (ROC) for chloride anions. The interaction with
γγγγ-aminobutyric acid (GABA) opens the channel. The influx of Cl– is
the cause of hyperpolarization of the postsynaptic membrane and thus
Cl–
the cause of hyperpolarization of the postsynaptic membrane and thus
its depolarization (formation of an action potential) disabled.
The receptor is a heteropentamer
(three subunit types). Besides the
α1
β2
β2
α1
(three subunit types). Besides the
binding site for GABA, it has at least
eleven allosteric modulatory sites for
compounds that enhance the response
–
–
γ2
compounds that enhance the response
to endogenous GABA – reduction of
anxiety and muscular relaxation:
–
–
–
–
–– –
anxiety and muscular relaxation:
anaesthetics, ethanol, and many useful
drugs, e.g. benzodiazepines (hence the
alternative name GABA/benzodiazepine receptors), meprobamate, and alsoalternative name GABA/benzodiazepine receptors), meprobamate, and also
barbiturates. Some ligands compete for the diazepam site or act as antagonists
(inverse agonists) so that they cause discomfort and anxiety, e.g. endogenous
peptides called endozepines.
In the spinal cord and the brain stem, glycine has the similar function as GABA in
the brain. The inhibitory actions of glycine are potently blocked by the alkaloid
peptides called endozepines.
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the brain. The inhibitory actions of glycine are potently blocked by the alkaloid
strychnine, a convulsant poison in man and animals.
Inhibitory synapse
GABA (γγγγ-aminobutyric acid) is the major inhibitory neurotransmitter in CNS.
Gabaergic synapses represent about 60 % of all synapses within the brain.
Inhibitory synapse
Gabaergic synapses represent about 60 % of all synapses within the brain.
Ca2+
depolarization wave
Ca2+
GABA
GABA / benzodiazepine
receptorsreceptors
mitochondrial synthesis
of GABA from glutamate
uptake of GABA into glial cells
and breakdown to succinate
partial reuptake
(transporters GAT 1,2,3,4)
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and breakdown to succinate
Receptors for the major neurotransmitters
Receptors cooperating with G-proteinsIon channels
(ROC) Gs (cAMP increase) Gi (cAMP decrease) Gq (IP3/DG formation)
Na+/K+ – acetylcholine
nicotinic
acetylcholine
muscarinic M2,4
adrenergic β1, β2, β3 adrenergic α2 adrenergic α1
acetylcholine
muscarinic M1,3,5
–
– adrenergic β1, β2, β3 adrenergic α2 adrenergic α1
Na+/Ca2+/K+
– glutamate ionophors
glutamate mGluR
group II and III
glutamate mGluR
group I–
–
dopamine D1,5 dopamin D3,4 dopamine D2
– serotonin 5-HT3 serotonin 5-HT4,6 serotonin 5-HT1 serotonin 5-HT2
–
– histamine H2 histamine H3,4 histamine H1
tachykinin NK-1
for substance P
– – –
Cl– – GABAA
– glycine
GABAB (metabotropic) – –
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