Transcript PowerPoint 演示文稿 - Shandong University

Section 2:
Signal Transmission Between the
Neurons
Neurotransmission
1.Chemical synapse (Classical Synapse)
– Predominates in the vertebrate nervous system
2.Non-synaptic chemical transmission
3.Electrical synapse
– Via specialized gap junctions
– Does occur, but rare in vertebrate NS
– Astrocytes can communicate via gap junctions
Chemical Synapse
• Terminal bouton is
separated from
postsynaptic cell by
synaptic cleft.
• Vesicles fuse with
axon membrane and
NT released by
exocytosis.
• Amount of NTs
released depends upon
frequency of AP.
Non-synaptic chemical transmission
The postganglionic
neurons innervate the
smooth muscles.
 No recognizable endplates
or other postsynaptic
specializations;
 The multiple branches are
beaded with enlargements
(varicosities) that are not
covered by Schwann cells
and contain synaptic vesicles;
Fig. : Ending of postganglionic
autonomic neurons on smooth
muscle
Non-synaptic chemical transmission continued
 In noradrenergic
neurons, the varicosities
are about 5m, with up to
20,000 varicosities per
neuron;
 Transmitter is apparently
released at each varicosity,
at many locations along
each axon;
 One neuron innervate
many effector cells.
Fig. : Ending of postganglionic
autonomic neurons on smooth
muscle
Electrical Synapse
• Impulses can be regenerated
without interruption in
adjacent cells.
• Gap junctions:
– Adjacent cells electrically
coupled through a
channel.
– Each gap junction is
composed of 12 connexin
proteins.
• Examples:
– Smooth and cardiac
muscles, brain, and glial
cells.
Electrical Synapses
•Electric current flowcommunication takes
place by flow of electric
current directly from one
neuron to the other
•No synaptic cleft or
vesicles cell membranes
in direct contact
•Communication not
polarized- electric current
can flow between cells in
either direction
Electrical Synapse
Chemical Synapse
Purves, 2001
I The Chemical Synapse and Signal
Transmission
• The chemical synapse is a specialized junction
that transfers nerve impulse information from a
pre synaptic membrane to a postsynaptic
membrane using neurotransmitters and enzymes
Synaptic connections
• ~100,000,000,000
neurons in human
brain
• Each neuron
contacts ~1000 cells
• Forms ~10,000
connections/cell
• How many
synapses?
•Neurotransmittercommunication via a
chemical intermediary Chemical Synapses
called a
neurotransmitter,
released from one
neuron and influences
another
•Synaptic cleft- a small
gap between the
sending (presynaptic)
and the receiving
(postsynaptic) site
•Synaptic vesiclessmall spherical or oval
organelles contain
Chemical Synapses
chemical transmitter
used in transmission
•Polarizationcommunication occurs
in only one direction,
from sending
presynaptic site, to
receiving postsynaptic
site
1. Synaptic Transmission Model
•
•
•
•
•
•
Precursor transport
NT synthesis
Storage
Release
Activation
Termination ~diffusion, degradation,
uptake, autoreceptors
Presynaptic
Axon Terminal
Terminal
Button
Postsynaptic
Membrane
Dendritic
Spine
(1) Precursor
Transport
(2)
Synthesis
_
_
_
enzymes/cofactors
NT
(3) Storage
in vesicles
NT
Terminal
Button
Dendritic
Spine
Synapse
Vesicles
(4) Release
Terminal
Button
Dendritic
Spine
Synapse
Receptors
Terminal
Button
AP
Dendritic
Spine
Synapse
Exocytosis
2+
Ca
Each vesicle contains one quanta of neurotransmitter
(approximately 5000 molecules) – quanta release
(5) Activation
(6) Termination
(6.1) Termination by...
Diffusion
(6.2) Termination by...
Enzymatic degradation
(6.3) Termination by...
Reuptake
(6.4) Termination by...
Autoreceptors
A
Autoreceptors
• On presynaptic terminal
• Binds NT
same as postsynaptic receptors
different receptor subtype
• Decreases NT release & synthesis
• Metabotropic receptors
Synaptic Transmission
• AP travels down axon to bouton.
• VG Ca2+ channels open.
– Ca2+ enters bouton down concentration
gradient.
– Inward diffusion triggers rapid fusion of
synaptic vesicles and release of NTs.
• Ca2+ activates calmodulin, which activates
protein kinase.
• Protein kinase phosphorylates synapsins.
– Synapsins aid in the fusion of synaptic vesicles.
Synaptic Transmission
(continued)
• NTs are released and diffuse across
synaptic cleft.
• NT (ligand) binds to specific receptor
proteins in postsynaptic cell membrane.
• Chemically-regulated gated ion channels
open.
– EPSP: depolarization.
– IPSP: hyperpolarization.
• Neurotransmitter inactivated to end
transmission.
2 EPSP and IPSP
(1)Excitatory
postsynaptic
potential (EPSP)
An AP arriving in the
presynaptic terminal
cause the release of
neurotransmitter;
The molecules bind
and active receptor on
the postsynaptic
membrane;
(1)Excitatory
postsynaptic
potential (EPSP)
Opening transmittergated ions channels
( Na+) in postsynapticmembrane;
Both an electrical and a
concentration gradient
driving Na+ into the cell;
The postsynaptic
membrane will become
depolarized(EPSP).
• No threshold.
• Decreases resting
membrane
potential.
– Closer to threshold.
• Graded in
magnitude.
• Have no refractory
period.
• Can summate.
EPSP
(2) Inhibitory
postsynaptic potential
(IPSP)
• A impulse
arriving in the
presynaptic terminal causes the
release of neurotransmitter;
•The molecular bind and active
receptors on the postsynaptic
membrane open CI- or,
sometimes K+ channels;
• More CI- enters, K+ outer the
cell, producing a
hyperpolarization in the
postsynaptic membrane.
•(IPSPs):
–No threshold.
–Hyperpolarize
postsynaptic
membrane.
–Increase membrane
potential.
–Can summate.
–No refractory period.
3 Synaptic Inhibition
• Presynaptic inhibition:
– Amount of
excitatory NT
released is decreased
by effects of second
neuron, whose axon
makes synapses with
first neuron’s axon.
• Postsynaptic inhibition
(1) Postsynaptic inhibition
 Concept: effect of inhibitory synapses on the
postsynaptic membrane.
 Mechanism: IPSP, inhibitory interneuron
 Types:
Afferent collateral inhibition( reciprocal
inhibition)
Recurrent inhibition.
1) Reciprocal inhibition
Postsynaptic inhibition
Activity in the afferent fibers
from the muscle spindles
(stretch receptors) excites
(EPSPs) directly the motor
neurons supplying the
muscle from which the
impulses come.
At the same time, inhibits (ISPSs) those
motor neurons supplying its antagonistic
muscles.
1) Reciprocal inhibition
Postsynaptic inhibition
The latter response is
mediated by
branches of the
afferent fibers that
end on the
interneurons.
The interneurons, in turn, secrete the inhibitory
transmitter (IPSP) at synapses on the proximal
dendrites or cell bodies of the motor neurons that
supply the antagonist.
Neurons may also inhibit
Postsynaptic
themselves in a negative feedback
fashion.
inhibition
2) Recurrent inhibition
Each spinal motor neuron regularly
gives off a recurrent collateral that
synapses with an inhibitory
interneuron which terminates on
the cell body of the spinal neuron
and other spinal motor neurons.
The inhibitory interneuron to
secrete inhibitory mediator, slows
and stops the discharge of the
motor neuron.
Concept: the inhibition occurs at the
presynaptic terminals before the
(2) Presynaptic
signal ever reaches the synapse.
inhibition
The basic structure: an axon-axon
synapse (presynaptic synapse), A
B
A
A
A
and B.
Neuron A has no direct effect on
B
neuron C, but it exert a
Presynaptic effect on ability of B
to Influence C.
C
C
The presynatic effect May decrease
the amount of neuro- transmitter
released from B (Presynaptic
inhibition) or increase it
(presynaptic facilitation).
Presynaptic inhibition
The mechanisms:
• Activation of the presynaptic
receptors increases CIconductance, 
to decrease the size of the AP
reaching the excitatory
ending, 
reduces Ca2+ entry and
consequently the amount of
excitatory transmitter
decreased.
• Voltage-gated
K+ channels
are also opened, and the
resulting K+ efflux also
decreases the Ca2+ influx.
Presynaptic Inhibition
Excitatory Synapse
A
+
• A active
• B more likely to fire
• Add a 3d neuron ~
B
Presynaptic Inhibition
Excitatory Synapse
A
-
+
C
• Axon-axon synapse
• C is inhibitory ~
B
Presynaptic Inhibition
Excitatory Synapse
A
-
+
B
C
• C active
• less NT from A when active
• B less likely to fire ~
4 Synaptic Facilitation: Presynaptic and
Postsynaptic
(1) Presynaptic Facilitation
Excitatory Synapse
A
+
• A active
• B more likely to fire ~
B
Presynaptic Facilitation
Excitatory Synapse
A
+
C
+
B
• C active (excitatory)
• more NT from A when
active (Mechanism:AP of A is
prolonged and Ca 2+ channels
are open for a longer period.)
• B more likely to fire ~
(2) Postsynaptic facilitation: neuron that has
been partially depolarized is more likely to
undergo AP.
Record here
EPSP
+
+
• Depolarization
more likely to fire ~
Vm
-65mv
- 70mv
AT REST
Time
• EPSPs can summate,
producing AP.
– Spatial summation:
• Numerous PSP
converge on a single
postsynaptic neuron
(distance).
– Temporal
summation:
• Successive waves of
neurotransmitter
release (time).
5 Synaptic
Integration
(1) Spatial Summation
• The accumulation of neurotransmitter in the
synapse due the combined activity of
several presynaptic neurons entering the
Area (Space) of a Convergent Synapse.
• A space (spatial) dependent process.
Spatial
Summation
+
+
+
• Multiple synapses
vm
-65mv
- 70mv
AT REST
Time
(2) Temporal Summation
• The accumulation of neurotransmitters in a
synapse due to the rapid activity of a
presynaptic neuron over a given Time
period.
• Occurs in a Divergent Synapse. (explain
later)
• Is a Time (Temporal) dependent process.
Temporal
Summation
+
+
Repeated stimulation
 same synapse ~

Vm
-65mv
- 70mv
AT REST
Time
(3) EPSPs & IPSPs summate
• CANCEL EACH OTHER
• Net stimulation
– EPSPs + IPSPs = net effects ~
+
+
- 70mv
-
EPSP
IPSP
6. Divergent and Convergent
Synapse
Divergent Synapse
•A junction that occurs between a presynaptic neuron
and two or more postsynaptic neurons (ratio of pre to
post is less than one).
•The stimulation
of the
postsynaptic
neurons depends
on temporal
summation).
Convergent Synapse
•A junction between
two or more
presynaptic neurons
with a postsynaptic
neuron (the ratio of
pre to post is greater
than one).
•The stimulation of
the postsynaptic
neuron depends on
the Spatial
Summation.
Presynaptic neurons
Postsynaptic
neuron
II Neurotransmitters and receptors
1. Basic Concepts of NT and receptor
Neurotransmitter: Endogenous signaling
molecules that alter the behaviour of neurons or
effector cells.
Neuroreceptor: Proteins on the cell membrane or in
the cytoplasm that could bind with specific
neurotransmitters and alter the behavior of neurons of
effector cells
•Vast array of molecules serve as neurotransmitters
•The properties of the transmitter do not determine its
effects on the postsynaptic cells
•The properties of the receptor determine whether a
transmitter is excitatory or inhibitory
A neurotransmitter must (classical definition)
•
•
•
•
•
Be synthesized and released from neurons
Be found at the presynaptic terminal
Have same effect on target cell when applied externally
Be blocked by same drugs that block synaptic transmission
Be removed in a specific way
Purves,
2001
Classical Transmitters
(small-molecule
transmitters)
•Biogenic Amines
•Acetylcholine
•Catecholamines
•Dopamine
•Norepinerphrine
•Epinephrine
•Serotonin
•Amino Acids
•Glutamate
•GABA (-amino butyric acid)
•Glycine
Non-classical Transmitters
•Neuropeptides
•Neurotrophins
•Gaseous messengers
–Nitric oxide
–Carbon Monoxide
•D-serine
Agonist
A substance that mimics a specific neurotransmitter,
is able to attach to that neurotransmitter's receptor
and thereby produces the same action that the
neurotransmitter usually produces.
Drugs are often designed as receptor agonists to treat a
variety of diseases and disorders when the original
chemical substance is missing or depleted.
Antagonist
Drugs that bind to but do not activate neuroreceptors,
thereby blocking the actions of neurotransmitters or
the neuroreceptor agonists.
• Same NT can bind to different -R
• different part of NT ~
NT
Receptor A
Receptor B
Specificity of drugs
Drug A
Receptor A
Drug B
NT
Receptor B
Five key steps in neurotransmission
• Synthesis
• Storage
• Release
• Receptor Binding
• Inactivation
Purves, 2001
Synaptic vesicles
• Concentrate and
protect transmitter
• Can be docked at
active zone
• Differ for classical
transmitters (small,
clear-core) vs.
neuropeptides (large,
dense-core)
Neurotransmitter Co-existence (Dale
principle)
Some neurons in both the PNS and CNS produce both a
classical neurotransmitter (ACh or a catecholamine) and a
polypeptide neurotransmitter.
They are contained in different synaptic vesicles that can be
distinguished using the electron microscope.
The neuron can thus release either the classical
neurotransmitter or the polypeptide neurotransmitter under
different conditions.
Purves, 2001
Receptors determine whether:
• Synapse is excitatory or inhibitory
– NE is excitatory at some synapses, inhibitory at
others
• Transmitter binding activates ion channel directly or
indirectly.
– Directly
• ionotropic receptors
• fast
– Indirectly
• metabotropic receptors
• G-protein coupled
• slow
2. Receptor Activation
• Ionotropic channel
– directly controls channel
– fast
• Metabotropic channel
– second messenger systems
– receptor indirectly controls channel ~
(1) Ionotropic Channels
Channel
NT
neurotransmitter
Ionotropic Channels
NT
Pore
Ionotropic Channels
NT
Ionotropic Channels
(2) Metabotropic Channels
• Receptor separate from channel
• G proteins
• 2d messenger system
– cAMP
– other types
• Effects
– Control channel
– Alter properties of receptors
– regulation of gene expression ~
(2.1) G protein: direct control
• NT is 1st messenger
• G protein binds to channel
– opens or closes
– relatively fast ~
G protein: direct control
R
G
GDP
G protein: direct control
R
G
GTP
Pore
(2.2) G protein: Protein Phosphorylation
external
external signal:
signal: NT
nt
norepinephrine
Receptor
b adrenergic -R
transducer
primary
effector
GS
adenylyl
cyclase
2d messenger
cAMP
secondary effector
protein kinase
G protein: Protein Phosphorylation
A
C
R
G
GDP
PK
G protein: Protein Phosphorylation
A
C
R
G
ATP
GTP
cAMP
PK
G protein: Protein Phosphorylation
A
C
R
G
ATP
GTP
P
cAMP
PK
Pore
(3) Transmitter Inactivation
•
•
•
•
•
•
Reuptake by presynaptic terminal
Uptake by glial cells
Enzymatic degradation
Presynaptic receptor
Diffusion
Combination of above
Summary of
Synaptic
Transmission
Purves,2001
Basic Neurochemistry
3. Some Important Transmitters
(1) Acetylcholine (ACh) as NT
Acetylcholine Synthesis
choline
acetyltransferase
choline + acetyl CoA
ACh + CoA
Acetylcholinesterase (AChE)
• Enzyme that
inactivates ACh.
– Present on
postsynaptic
membrane or
immediately outside
the membrane.
• Prevents continued
stimulation.
The Life Cycle of Ach
Ach - Distribution
• Peripheral N.S.
• Excites somatic skeletal muscle (neuro-muscular
junction)
• Autonomic NS
Ganglia
Parasympathetic NS--- Neuroeffector junction
Few sympathetic NS – Neuroeffector junction
• Central N.S. - widespread
Hippocampus
Hypothalamus ~
Ach Receptors
•ACh is both an excitatory and inhibitory NT, depending on
organ involved.
–Causes the opening of chemical gated ion channels.
•Nicotinic ACh receptors:
–Found in autonomic ganglia (N1) and skeletal muscle fibers (N2).
•Muscarinic ACh receptors:
–Found in the plasma membrane of smooth and cardiac muscle
cells, and in cells of particular glands .
Acetylcholine Neurotransmission
• “Nicotinic” subtype Receptor:
– Membrane Channel for Na+ and K+
– Opens on ligand binding
– Depolarization of target (neuron, muscle)
– Stimulated by Nicotine, etc.
– Blocked by Curare, etc.
– Motor endplate (somatic) (N2),
– all autonomic ganglia, hormone
producing cells of adrenal medulla (N1)
Acetylcholine Neurotransmission
• “Muscarinic” subtype Receptor: M1
– Use of signal transduction system
• Phospholipase C, IP3, DAG, cytosolic Ca++
– Effect on target: cell specific (heart , smooth
muscle intestine )
– Blocked by Atropine, etc.
– All parasympathetic target organs
– Some sympathetic targets (endocrine sweat
glands, skeletal muscle blood vessels - dilation)
Acetylcholine Neurotransmission
• “Muscarinic” subtype: M2
– Use of signal transduction system
• via G-proteins, opens K+ channels, decrease
in cAMP levels
– Effect on target: cell specific
– CNS
– Stimulated by ?
– Blocked by Atropine, etc.
Cholinergic Agonists
• Direct
– Muscarine
– Nicotine
• Indirect
– AChE Inhibitors ~
Cholinergic Antagonists
• Direct
Nicotinic - Curare
Muscarinic - Atropine
Ligand-Operated ACh Channels
N Receptor
M
receptor
G Protein-Operated ACh Channel
(2) Monoamines as NT
Monoamines
• Catecholamines –
Dopamine - DA
Norepinephrine - NE
Epinephrine - E
• Indolamines Serotonin - 5-HT
Mechanism of Action (b receptor)
Epi
a1
G protein
PLC
IP3
Ca+2
Norepinephrine (NE) as NT
• NT in both PNS and CNS.
• PNS:
– Smooth muscles, cardiac muscle and glands.
• Increase in blood pressure, constriction of arteries.
• CNS:
– General behavior.
Adrenergic Neurotransmission
• a1 Receptor
– Stimulated by NE, E,
– blood vessels of skin, mucosa, abdominal
viscera, kidneys, salivary glands
– vasoconstriction, sphincter constriction, pupil
dilation
Adrenergic Neurotransmission
• a2 Receptor
– stimulated by, NE, E, …..
– Membrane of adrenergic axon terminals (presynaptic receptors), platelets
– inhibition of NE release (autoreceptor),
– promotes blood clotting, pancreas decreased
insulin secretion
Adrenergic Neurotransmission
• b1 receptor
– stimulated by E, ….
– Mainly heart muscle cells,
– increased heart rate and strength
Adrenergic Neurotransmission
•
b 2 receptor
– stimulated by E ..
– Lungs, most other sympathetic organs, blood
vessels serving the heart (coronary vessels),
– dilation of bronchioles & blood vessels
(coronary vessels), relaxation of smooth muscle
in GI tract and pregnant uterus
Adrenergic Neurotransmission
• b 3 receptor
– stimulated by E, ….
– Adipose tissue,
– stimulation of lipolysis
(3) Amino Acids as NT
• Glutamate acid and aspartate acid:
– Excitatory Amino Acid (EAA)
• gamma-amino-butyric acid (GABA) and
glycine:
– Inhibitory AA
(4) Polypeptides as NT
• CCK:
– Promote satiety following meals.
• Substance P:
– Major NT in sensations of pain.
(5) Monoxide Gas: NO and CO
• Nitric Oxide (NO)
– Exerts its effects by stimulation of cGMP.
– Involved in memory and learning.
– Smooth muscle relaxation.
• Carbon monoxide (CO):
– Stimulate production of cGMP within neurons.
– Promotes odor adaptation in olfactory neurons.
– May be involved in neuroendocrine regulation in
hypothalamus.