Download Events at a chemical synapse

NEUROBIOCHEMISTRY
SYNAPSE
AND
NEUROTRANSMITTER
MOHAMMAD HANAFI
Synapses
• A junction that mediates information transfer
from one neuron:
– To another neuron
– To an effector cell
• Presynaptic neuron – conducts impulses
toward the synapse
• Postsynaptic neuron – transmits impulses
away from the synapse
The Synapse
• Junction between
two cells
• Site where action
potentials in one cell
cause action
potentials in another
cell
• Types of cells in
synapse
– Presynaptic
– Postsynaptic
Synapses
1. Axodendritic synapse
2. Axosomatic synapse
3. Axoaxonic synapse
Figure 11.17
Electrical Synapses
• Gap junctions that allow
local current to flow between
adjacent cells. Connexons:
protein tubes in cell
membrane.
• Found in cardiac muscle and
many types of smooth
muscle. Action potential of
one cell causes action
potential in next cell, almost
as if the tissue were one cell.
• Important where contractile
activity among a group of
cells important.
Chemical Synapses
• Components
– Presynaptic terminal
– Synaptic cleft
– Postsynaptic membrane
• Neurotransmitters released by action potentials in
presynaptic terminal
– Synaptic vesicles: action potential causes Ca 2+ to enter
cell that causes neurotransmitter to be released from
vesicles
– Diffusion of neurotransmitter across synapse
– Postsynaptic membrane: when ACh binds to receptor,
ligand-gated Na+ channels open. If enough Na+ diffuses into
postsynaptic cell, it fires.
Chemical Synapse
Events at a chemical synapse
1. Arrival of nerve impulse opens
volage-gated calcium channels.
2. Ca++ influx into presynaptic term.
3. Ca++ acts as intracellular messenger
stimulating synaptic vesicles to fuse with
membrane and release NT via exocytosis.
4. Ca++ removed from terminal by
mitochondria or calcium-pumps.
5. NT diffuses across synaptic cleft and
binds to receptor on postsynaptic memb
6. Receptor changes shape of ion channel
opening it and changing membrane potential
7. NT is quickly destroyed by enzymes or
taken back up by astrocytes or presynaptic
membrane.
Note: For each nerve impulse reaching the
presynaptic terminal, about 300 vesicles
are emptied into the cleft.
Neurotransmitter Removal
• Method depends on neurotransmitter/synapse.
• ACh: acetylcholinesterase splits ACh into acetic acid
and choline. Choline recycled within presynaptic
neuron.
• Norepinephrine: recycled within presynaptic neuron
or diffuses away from synapse. Enzyme monoamine
oxidase (MAO). Absorbed into circulation, broken
down in liver.
Removal of Neurotransmitter
from Synaptic Cleft
Receptor Molecules and
Neurotransmitters
• Neurotransmitter only "fits" in one receptor.
• Not all cells have receptors.
• Neurotransmitters are excitatory in some cells
and inhibitory in others.
• Some neurotransmitters (norepinephrine)
attach to the presynaptic terminal as well as
postsynaptic and then inhibit the release of
more neurotransmitter.
Neurotransmitters found in the nervous system
EXCITATORY
Acetylcholine
Aspartate
Dopamine
Histamine
Norepinephrine
Epinephrine
Glutamate
Serotonin
INHIBITORY
GABA
Glycine
Neurotransmitters
• Chemicals used for neuronal communication
with the body and the brain
• 50 different neurotransmitters have been
identified
• Classified chemically and functionally
– Chemically:
• ACh, Biogenic amines, Peptides
– Functionally:
• Excitatory or inhibitory
• Direct/Ionotropic (open ion channels) or
Indirect/metabotropic (activate G-proteins) that
create a metabolic change in cell
Chemical Neurotransmitters
•
•
•
•
•
Acetylcholine (ACh)
Biogenic amines
Amino acids
Peptides
Novel messengers: ATP and dissolved
gases NO and CO
Neurotransmitters: Acetylcholine
•
•
•
•
•
First neurotransmitter identified, and best understood
Released at the neuromuscular junction
Synthesized and enclosed in synaptic vesicles
Degraded by the enzyme acetylcholinesterase (AChE)
Released by:
– All neurons that stimulate skeletal muscle
– Some neurons in the autonomic nervous system
• Binds to cholinergic receptors known as nicotinic or
muscarinic receptors
– Nicotinic receptors
– Neuromuscular junction of skeletal muscles
Acetylcholine synthesis:
• In the cholinergic neurons acetylcholine is
synthesized from choline. This reaction is
activated by cholineacetyltransferase
As soon as acetylcholine is synthesized,
it is stored within synaptic vesicles.
Structure of AchE
• Acetylcholinesterase (AchE) is an
enzyme, which hydrolyses the
neurotransmitter acetylcholine. The
active site of AChE is made up of two
subsites, both of which are critical to the
breakdown of ACh. The anionic site
serves to bind a molecule of ACh to the
enzyme. Once the ACh is bound, the
hydrolytic reaction occurs at a second
region of the active site called the
esteratic subsite. Here, the ester bond of
ACh is broken, releasing acetate and
choline. Choline is then immediately
taken up again by the high affinity
choline uptake system on the presynaptic
membrane.
Cholinergic Receptors
• Nicotinic receptors
- On neuromuscular junction of skeletal muscle
- On all ganglionic neurons of autonomic nervous system
- Excitatory
• Muscarinic receptors
- All parasympathetic target organs (cardiac and smooth
muscle)
- Exciatory in most cases
Acetylcholine
• Effects prolonged (leading to tetanic muscle
spasms and neural “frying”) by nerve gas and
organophosphate insecticides (Malathion).
• ACH receptors destroyed in myasthenia
gravis
• Binding to receptors inhibited by curare (a
muscle paralytic agent-blowdarts in south
American tribes) and some snake venoms.
FUNCTIONS OF ACh
1. Acetylcholine is involved in a variety of functions
including pain, recent memory, nicotine addiction,
salivation, locomotion, regulation of circadian
rhythm and thermoregulation.
2. It has also been demonstrated that brain
cholinergic neurons play a critical role in
Alzheimer’s disease, Huntington’s chorea and in
the generation of epileptic seizures.
Neurotransmitters:
Biogenic Amines
• Include:
– Catecholamines – dopamine, norepinephrine
(NE), and epinephrine (EP)
– Indolamines – serotonin and histamine
• Broadly distributed in the brain
• Play roles in emotional behaviors and our
biological clock
Synthesis of Catecholamines
• AA tyrosine parent cpd
• Enzymes present in the
cell determine length of
biosynthetic pathway
• Norepinephrine and
dopamine are
synthesized in axonal
terminals
• Epinephrine is released
by the adrenal medulla
as a hormone
Figure 11.22
BIOGENIC AMINES
• Norepinephrine (aka Noradrenaline)
– Main NT of the sympathetic branch of autonomic nervous system
– Binds to adrenergic receptors ( or  -many subtypes, 1, 2, etc)
– Excitatory or inhibitory depending on receptor type bound
– “Feeling good” NT
– Release enhanced by amphetamines
– Removal from synapse blocked by antidepressants and cocaine
• Dopamine
– Binds to dopaminergic receptors of substantia nigra of midbrain
and hypothalamus
– “Feeling good” NT
– Release enhanced by amphetamines
– Reuptake block by cocaine
– Deficient in Parkinson’s disease
– May be involved in pathogenesis of schizophrenia
Serotonin (5-HT)
• Synthesized from a.a. tryptophan
The synthesis of serotonin involve two reactions:
1) Hydroxylation:
Tryptophan
5- Hydroxytryptophan
The enzyme catalyzes this reaction is
Tryptophan Hydroxylase.
The Co- factor is Tetrahydrobiopterin, which
converted in this reaction to Dihydrobiopterin
2) Decarboxylation:
5- hydroxytryptophan
Serotonin
The enzyme is hydroxytryptophan
decarboxylase.
Serotonin is synthesized in CNS, &
Chromaffin cells.
Break down of serotonin:
• Serotonin is degraded in two recations
1) Oxidation:
5-hydroxytryptoamine + O2 + H2O
5- Hydroxyinodole-3Monoamine oxidase
acetaldehyde
2) Dehydrogenation
5- Hydroxyinodole-3-acetaldehyde Aldehyde dehydrogenase
5-hydroxindole-3-acetate
(Anion of 5-hydroxyindoleacetic acid)
May play a role in sleep, appetite, and
regulation of moods
Drugs that block its uptake relieve
anxiety and depression
SSRI’s = selective serotonin reuptake
inhibitors
Include drugs such as Prozac,
Celexa, Lexapro, Zoloft
Neurotransmitters:
Amino Acids
• Include:
– GABA – Gamma ()-aminobutyric acid
– Glycine
– Aspartate
– Glutamate
• Found only in the CNS
Amino Acids
GABA
• Main inhibitory neurotransmitter in the brain
• Inhibitory effects augmented by alcohol and antianxiety
drugs like Valium
• Increases influx of Cl- in postsynaptic neuron,
hyperpolarising it and thus inhibiting it!
GLUTAMATE
* Widespread in brain where it represents the major
excitatory neurotransmitter
• Important in learning and memory
• “Stroke NT” -excessive release produces excitotoxicity:
neurons literally stimulated to death; most commonly
caused by ischemia due to stroke (Ouch!)
• Aids tumor advance when released by gliomas (ouch!)
SYNTHESIS AND RELEASE OF GLUTAMATE
NMDA RECEPTOR
FUNCTIONS OF GLUTAMATE
1. Glutamate acts as the major excitatory transmitter in
the brain
2. Excess glutamate causes neuronal damage and death,
principally by elevating cellular Ca+2. This phenomenon
has significance for a number of pathologies such as
Alzheimer’s disease, ALS, Ischemia and Hypoxia,
Epilepsy and Schizophrenia.
3. Glutamate receptors are involved in a physiological
phenomenon called long-term potentiation (LTP) - a
cellular model of learning and memory. The NMDA
receptor activation is an absolute requirement for
LTP induction, however, AMPA and metabotropic
glutamate receptors also play important roles.
SYNTHESIS AND RELEASE OF GABA
GABA
Gambar 46. Metabolisme γ amino butirat
Catatan: PLP = piridoksal fosfat.
GABAA RECEPTOR
FUNCTIONS OF GABA
1. GABA acts as the major inhibitory transmitter
in the brain
2. GABA has been implicated in several neurological and
psychiatricdisorders of humans including Huntington’s
chorea, epilepsy, alcoholism, Parkinson’s disease and
anxiety disorders.
3. Antiepileptic and anxiolytic properties of
benzodiazepine and phenobarbital suggest an
important role of GABA in epilepsy as well as
anxiety disorders.
Neurotransmitters: Peptides
• Include:
– Substance P – mediator of pain signals
– Beta endorphin, dynorphin, and enkephalins
• Act as natural opiates, reducing our perception
of pain
– Found in higher concentrations in marathoners and
women who have just delivered
• Bind to the same receptors as opiates and
morphine
Neurotransmitters: Novel Messengers
• Nitric oxide (NO)
– A short-lived toxic gas; diffuses through post-synaptic
membrane to bind with intracellular receptor
(guanynyl cyclase)
– Is involved in learning and memory
– Some types of male impotence treated by stimulating
NO release (Viagra)
• Viagra  NO release  cGMP  smooth muscle relaxation
 increased blood flow  erection
• Can’t be taken when other pills to dilate coronary b.v. taken
• Carbon monoxide (CO) is a main regulator of
cGMP in the brain
Summary:
Neurotransmitter
Molecule
Derived
From
Site of Synthesis
Acetylcholine
Choline
CNS, parasympathetic nerves
Serotonin
5-Hydroxytryptamine (5-HT)
Tryptophan
CNS, chromaffin cells of the gut, enteric
cells
GABA
Glutamate
CNS
Histamine
Histidine
hypothalamus
Epinephrine
synthesis pathway
Tyrosine
adrenal medulla, some CNS cells
Norpinephrine
synthesis pathway
Tyrosine
CNS, sympathetic nerves
Dopamine
synthesis pathway
Tyrosine
CNS
Nitric oxide, NO
Arginine
CNS, gastrointestinal tract