Transcript Neurotransmission

Neurotransmission
A nerve impulse initiated in a neuronal cell body,
conducted through it’s axons up to the nerve ending and
transmitted to other neuronal cells in succession and
finally to the target cells.
Target
cell
(Muscle
cells)
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Neurotransmission takes place by
a) Electrical synapse b) Chemical synapse
Electrical and chemical synapses differ fundamentally in their
transmission mechanisms.
A. At electrical synapses, gap junctions between pre- and postsynaptic
membranes permit current to flow passively through intercellular channels.
This current flow changes the postsynaptic membrane potential, initiating (or
in some instances inhibiting) the generation of postsynaptic action potentials.
B. At chemical synapses, there is no intercellular continuity, and thus no direct
flow of current from pre- to postsynaptic cell. Synaptic current flows across
the postsynaptic membrane only in response to the secretion of
neurotransmitters which open or close postsynaptic ion channels after binding
to receptor molecules.
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Neurotransmission in through chemical
synapse is mediated by Neurotransmitters
Neurotransmitters are chemical signals released from pre synaptic
nerve terminals into the synaptic cleft. The subsequent binding of
neurotransmitters to specific receptors on postsynaptic neurons (or
other classes of target cells) transiently changes the electrical
properties of the target cells, leading to an enormous variety of
postsynaptic effects.
Criteria That Define a Neurotransmitter
1. The substance must be stored in the nerve endings.
2. The substance must be released in response to presynaptic depolarization,
into the synaptic cleft and the release must be Ca2+-dependent.
3. Specific receptors for the substance must be present on the postsynaptic cell
4. Mechanism must be present in the synaptic region for the rapid removal of
the substances.
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Demonstrating the identity of a neurotransmitter at a synapse requires
showing (1) its presence, (2) its release, and (3) the postsynaptic presence of
specific receptors
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Localization of neurotransmitter action. Neurotransmitters in general act either
locally (A), by altering the electrical excitability of a small region of a single
postsynaptic cell, or more diffusely (B), by altering the electrical excitability of a
few postsynaptic cells. (C) Neurons can exert their actions over greater distances by
having long axons that locally release neurotransmitters onto distant targets.
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Mechanism of
neurotransmitter
release
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A model for Ca2+-triggered vesicle fusion. SNARE proteins on the synaptic
vesicle and plasma membranes form a complex that brings together the two
membranes. Ca2+ then binds to synaptotagmin on the vesicle membrane, causing
the cytoplasmic region of this protein to insert into the plasma membrane and
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catalyze membrane fusion.
Toxins That Affect Transmitter Release
Tetanus toxin and
botulinum toxin (types B,
D, F, and G) specifically
cleave the vesicle SNARE
protein, synaptobrevin.
Other botulinum toxins
are proteases that cleave
syntaxin (type C) and
SNAP-25 (types A and E),
SNARE proteins found on
the presynaptic plasma
membrane. Destruction of
these presynaptic proteins
is the basis for the actions
of the toxins on
neurotransmitter release.
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Chain of events
Action potential reaches the nerve ending
Nerve ending membrane depolarizes
Voltage gated Ca2+ channel opens and Ca2+ enters into the nerve endings
Synaptic vesicles are fused with nerve ending membrane with the help of
SNARE complex and this fusion is triggered by Ca2+
Neurotransmitters are released from the synaptic vesicle into the synaptic
cleft
Neurotransmitters binds with the specific receptors located in the post
synaptic membrane
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Neurons Often Release More Than One Transmitter
 Low-frequency stimulation
preferentially raises the Ca2+
concentration close to the
membrane,
favoring
the
release of transmitter from
small clear-core vesicles
docked
at
presynaptic
specializations.
 High-frequency stimulation
leads to a more general
increase in Ca2+, causing the
release of peptide neuro
transmitters from large densecore vesicles as well as smallmolecule
neurotransmitters
from small clear-core vesicles.
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End of lecture 1
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Major Categories of Neurotransmitters
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A neurotransmitter can affect the activity of a postsynaptic cell via two different
types of receptor proteins: ionotropic or ligand-gated ion channels, and
metabotropic receptors. (A) Ligand-gated ion channels combine receptor and
channel functions in a single protein complex. (B) Metabotropic receptors usually
activate G-proteins, which modulate ion channels directly or indirectly through
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intracellular effector enzymes and second messengers.
Neurotransmitter can induce two types of response
based on the property of the receptor
1) It may depolarize the post synaptic membrane giving rise to
Excitatory post synaptic potential (EPSP)
2) It may hyperpolarize the post synaptic membrane giving rise to
Inhibitory post synaptic potential (IPSP)
The nature of the post synaptic potential (EPSP pr IPSP)
depends upon the nature of the receptor not on the
neurotransmitter itself. Thus the same neurotransmitter may
have excitatory at one synapse and inhibitory at other. For ex
Acetylcholine.
It exerts IPSP at heart muscle but EPSP at neuro-muscular
junction.
It is known as Dale’s principle
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Removal of the neurotransmitters
in synaptic cleft
1) Enzymatic hydrolysis of neurotransmitters in the synaptic junctions.
Ex: a) Acetylcholine is hydrolyzed by the Acetylcholine esterase
b) Nucleotidase is involved in the degradation of ATP in synapse.
2) Reuptake of neurotransmitters from the synaptic cleft by the specific
receptor located in the pre-synaptic membrane or in adjacent glial cells.
Ex: Aminergic neurotransmitters such as epinephrine, nor epinephrine and
serotonin are reuptaken shortly after their release into synaptic cleft.
3) Photolytic cleavage of the peptide neurotransmitters or neuropeptides.
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Neurotransmitter Release and Removal
Neurotransmitter
Postsynaptic
effect
Rate-limiting step in
synthesis
Removal
mechanism
Type of
vesicle
ACh
Excitatory
Choline +
acetyl CoA
CAT
AChEase
Small, clear
Glutamate
Excitatory
Glutamine
Glutaminase
Transporters
Small, clear
GABA
Inhibitory
Glutamate
GAD
Transporters
Small, clear
Glycine
Inhibitory
Serine
Phosphoserine
Transporters
Small, clear
Catecholamines
(epinephrine,
norepinephrine,
dopamine)
Excitatory
Tyrosine
Tyrosine
hydroxylase
Transporters,
MAO, COMT
Small densecore, or large
irregular
dense-core
Serotonin (5-HT)
Excitatory
Tryptophan
Tryptophan
hydroxylase
Transporters,
MAO
Large,
dense-core
Histamine
Excitatory
Histidine
Histidine
decarboxylase
Transporters
Large,
dense-core
ATP
Excitatory
ADP
Mitochondrial
oxidative
phosphorylation;
glycolysis
Hydrolysis to
AMP and
adenosine
Small, clear
Neuropeptides
Excitatory
and inhibitory
Amino acids
(protein
synthesis)
Synthesis and
transport
Proteases
Large,
dense-core 17
Precursor(s)
Neurotransmitter Synthesis
The Biogenic Amines
There are five established biogenic
amine neurotransmitters: the three
catecholamines—dopamine,
norepinephrine (noradrenaline),
and epinephrine (adrenaline)—and
histamine and serotonin.
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Histamine and Serotonin
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Degradation
Neural : Through the action of Mono amine oxidase (MAO)
Extra neural: Through Catecholamine O methyl transferase
Biogenic Amine Neurotransmitters and Psychiatric Disorders
Reserpine: it blocks the vesicular monoamine transporter (VMAT) which normally
transport free nor epinephrine , dopamine and serotonin from the cytoplasm into synaptic
vesicle in the post synaptic nerve endings thus ultimately inhibits the release of these
neurotransmitters into synaptic cleft.
USE: to control high blood pressure. Side effects: Change of mood, Depression etc.
MAO inhibitors: MAO inhibitors such as phenelzine block the breakdown of amines,
serotonin uptake blockers such as fluoxetine (Prozac®) and trazodone—all influence
various aspects of aminergic transmission. The extraordinarily popular antidepressant
fluoxetine (Prozac®) selectively blocks the reuptake of serotonin without affecting the
reuptake of catecholamines.
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GABA
 The enzymes required for
this degradation, GABA
aminotransferase
and
succinic
semialdehyde
dehydrogenase, are both
mitochondrial enzymes.
 Inhibition
of
GABA
breakdown causes a rise in
tissue GABA content and an
increase in the activity of
inhibitory neurons.
 Drugs that act as agonists
or modulators on receptors,
such as benzodiazepines and
barbiturates, are effective
sedatives and anesthetics.
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Glycine
Glycine can be synthesized
by a number of metabolic
pathways; in the brain, the
major precursor is serine.
High-affinity transporters
terminate the actions of
these transmitters and
return GABA or glycine to
the synaptic terminals for
reuse.
Mutations in the genes coding
for some of these enzymes
result in hyperglycinemia, a
devastating neonatal disease
characterized
by
lethargy,
seizures,
and
mental
retardation.
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Glutamate
Glutamate is a nonessential amino acid that does not cross the blood-brain barrier
and must be synthesized in neurons from local precursors. The most prevalent
glutamate precursor in synaptic terminals is glutamine. Glutamine is released by
glial cells and, once within presynaptic terminals, is metabolized to glutamate by
the mitochondrial enzyme glutaminase.
Glutamate synthesis and
cycling between neurons
and glia. The action of
glutamate released into
the synaptic cleft is
terminated by uptake into
neurons and surrounding
glial cells via specific
transporters. Within the
nerve
terminal,
the
glutamate released by
glial cells and taken up
by neurons is converted
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back to glutamine.
Acetylcholine
Acetylcholine
is
the
neurotransmitter at neuromuscular
junctions, at synapses in the
ganglia of the visceral motor
system, and at a variety of sites
within the central nervous system.
Acetylcholine is synthesized in
nerve terminals from acetyl
coenzyme A (acetyl CoA, which is
synthesized from glucose) and
choline, in a reaction catalyzed by
choline acetyltransferase (CAT).
In contrast to most other small-molecule neurotransmitters, the postsynaptic action
of ACh at many cholinergic synapses (the neuromuscular junction in particular) are
not terminated by reuptake but by a powerful hydrolytic enzyme, AChE.
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Acetylcholine esterase inhibitors
Diisoproplyphosphofluorine
Succinyl choline
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Cholinergic receptor
The AchR is a pentameric supermolecule structure formed by 2 α, 1 β, 1γ and 1 δ
subunits. Each receptor subunit crosses the membrane four times. 2 molecules of
acetylcholine bind with each of 2 α chain leading to the transient opening of Na+
channels of the postsynaptic membrane. The openings at either end of the channel
are very large—approximately 3 nm in diameter; even the narrowest region of the
pore is approximately 0.6 nm in diameter. By comparison, the diameter of Na+ or
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K+ is less than 0.3 nm.
Inhibitors of Cholinergic receptor
Active compound in cuarare is d-tubocurarine: Interacts
reersibly with cholinergic receptor at the
neuromuscular junction.
Other inhibitors are neurotoxins found in venoms of
various poisonous snakesn. Ex: Alpha Bungarotoxin of
Bungaris multicinctus and Cobra toxin from Cobra
snake.
Agonists: Nicotine, Muscarine
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End of lecturer 2
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GABA receptor
GABA is the major inhibitory neurotransmitter in the mammalian CNS and,
like glutamate and other transmitters, acts via both ligand gated ion channels
(GABAA receptors) and G-protein coupled (GABAB) receptors. GABAA
receptors are members of the ionotropic receptor superfamily which includes
a-adrenergic and glycine receptors, while the GABAB receptor is a member of
the receptor superfamily including the Glu receptors.
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Dopaminergic receptor
2 types of Dopaminergic receptor have been identified
a) D1 which is involved in the enhancement of the
adenylate cyclase activity and is blocked selecting by
phenothiazine tranquilizers such as trifluoperazine.
b) D2 is associated with a reduction of adenylate cyclase
acitivity and is blocked by butyrophenone
neuroleptics such as haloperidol and spiperone. D2
subtype of dopaminergic receptor but not D1 are
cleosely related to the antipsychotic action of the
neuroleptic drug due to the related affinity of the
drug for D2.
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D1-like Dopamine receptor structure: 3 major segments. 1 extracellular chain,
3 Extracellular loops (E1-E3); 7 Transmembrane domains (1-7); 2
Intracellular loops (I2-I3) and 1 intracellular chain. Residues involved in
dopamine binding are highlighted in transmembrane domains: Phe and Ser.
Potential phosphorylation sites are represented on 3rd intracellular loop (I3)
and on COOH terminus. Potential glycosylation sites are represented on NH2
terminal.
D2-like receptors are characterized by a shorter COOH-terminal tail.
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Adrenergic receptor
2 major types of adrenergic receptors are known in the nervous system: α and β.
Each type exists in subtypes: α1 and α2; β1 and β2.
α1 receptor is postsynaptic in the sympathetic system. α2 is mainly presynaptic in
the extra neural region and regulates the release the nor-epinephrine while in
central nervous system α2 is mainly postsynaptic. Both β1 and β2 receptors are
postsynaptic in brain
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Receptor
type
Agonist potency
order
α1:
norepinephrine ≥
epinephrine >>
isoproterenol
α2:
β1
β2
norepinephrine ≥
epinephrine >>
isoproterenol
isoprenaline >
epinephrine =
norepinephrine
isoprenaline >
epinephrine >>
norepinephrine
Selected
action
of agonist
smooth muscle
contraction
Mechanism
Phospholipase C
(PLC) activated,
IP3 and calcium
up
smooth muscle
contraction and
neurotransmitter
inhibition
Adenylate
cyclase
inactivated,
cAMP down
heart muscle
contraction
Adenylate
cyclase activated,
cAMP up
smooth muscle
relaxation
Adenylate
cyclase activated,
cAMP up
Agonists
Antagonists
Phenylephrine
Methoxamine
Alfuzosin
Doxazosin
Phenoxybenzami
ne
Dexmedetomidin
e
Clonidine
Lofexidine
•Noradrenaline
•Isoprenaline
•Dobutamine
Salbutamol
Albuterol
•Bitolterol
mesylate
•Formoterol
•Isoprenaline
Yohimbine
Idazoxan
• Metoprolol
•Atenolol
•Practato
•Butoxamine
•Propranolol
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Peptide Neurotransmitters
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Peptide Neurotransmitter
propeptide precursors are typically larger than their active peptide products and can
give rise to more than one species of neuropeptide. Hence, the release of multiple
neuroactive peptides from a single vesicle often elicits complex postsynaptic
responses.
The maturation of the prepropeptides
involves
cleaving
the
signal
sequence
and
other
proteolytic
processing.
Such processing can result
in a number of different
neuroactive peptides such
as ACTH, γ-lipotropin,
and β-endorphin (A), or
multiple copies of the
same peptide, such as metenkephalin (B).
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Functions of neuropeptides
Neurotensin has been implicated in the modulation of dopamine signaling
As a neuropeptide, CCK mediates satiety by acting on the CCK receptors distributed
widely throughout the central nervous system. In humans, it has been suggested that
CCK administration causes nausea and anxiety. CCK also has stimulatory effects on
the vagus nerve, effects that can be inhibited by capsaicin.
Substance P is one of the important complex mechanisms involved in pain
perception.The sensory function of substance P is thought to be related to the
transmission of pain information into the central nervous system.
Somatostatin is produced by neuroendocrine neurons of the periventricular nucleus
of the hypothalamus. Then somatostatin is released from neurosecretory nerve
endings into the hypothalamo-hypophysial portal circulation. These blood vessels
carry somatostatin to the anterior pituitary gland, where somatostatin inhibits the
secretion of growth hormone from somatotrope cells.
An enkephalin is a pentapeptide involved in regulating pain in the body.
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