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• ~100,000,000,000
neurons in human
brain
• Each neuron
contacts ~1000 cells
• Forms ~10,000
connections/cell
• How many synapses?
•Neurotransmitter-
communication 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 vesicles-
small spherical or oval
organelles contain Chemical Synapses
chemical transmitter
used in transmission
•Polarization-
communication 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 Postsynaptic
Axon Terminal Membrane
Terminal
Button 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 Dendritic
Spine
AP Synapse
Exocytosis
Ca2+
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)
• 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
A + B
• A active
• B more likely to fire
• Add a 3d neuron ~
Presynaptic Inhibition
Excitatory Synapse
A + B
-
C
• Axon-axon synapse
• C is inhibitory ~
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 + B
• A active
• B more likely to fire ~
Presynaptic Facilitation
Excitatory Synapse
A + B
+
• C active (excitatory)
C
• 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
Vm more likely to fire ~
-65mv
- 70mv AT REST
-
Time
• EPSPs can summate, 5 Synaptic
producing AP. Integration
– Spatial summation:
• Numerous PSP
converge on a single
postsynaptic neuron
(distance).
– Temporal
summation:
• Successive waves of
neurotransmitter
release (time).
(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 ~
EPSP
+
-
IPSP
+
- 70mv
-
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
presynaptic neurons
with a postsynaptic
neuron (the ratio of
pre to post is greater
than one).
•The stimulation of
the postsynaptic
neuron depends on Postsynaptic
the Spatial neuron
Summation.
II Neurotransmitters and receptors
1. Basic Concepts of NT and receptor
Purves,
2001
Classical Transmitters
(small-molecule transmitters) Non-classical Transmitters
•Biogenic Amines
•Acetylcholine
•Neuropeptides
•Catecholamines
•Neurotrophins
•Dopamine
•Gaseous messengers
•Norepinerphrine
–Nitric oxide
•Epinephrine
–Carbon Monoxide
•Serotonin
•D-serine
•Amino Acids
•Glutamate
•GABA (-amino butyric acid)
•Glycine
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 B
Drug A
NT
Receptor A 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
trans- primary adenylyl
GS
ducer effector cyclase
2d messenger cAMP
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
Purves,2001
Basic Neurochemistry
3. Some Important Transmitters
(1) Acetylcholine (ACh) as NT
Acetylcholine Synthesis
choline
acetyltransferase
• 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 G Protein-Operated ACh Channel
receptor
(2) Monoamines as NT
Monoamines
• Catecholamines – • Indolamines -
Dopamine - DA Serotonin - 5-HT
Norepinephrine - NE
Epinephrine - E
Mechanism of Action (b receptor)
Epi
a1
G protein
PLC IP3
Ca+2
Norepinephrine (NE) as NT
• 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
• 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
• 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.