FUNDAMENTALS 1: 10:00-11:00
9/20/2010
THEIBERT
NEUROTRANSMITTERS
SCRIBE: KRATIKA PAREEK
PROOF: ANGI GULLARD
PAGE 1 OF 11
I.
NEUROTRANSMITTERS [S3]
a. Neurochemistry is thought to be a subdivision of 2 different types of specialties. They
include biochemistry and neuroscience. Neuroscience has to do with the brain, PNS
(peripheral nervous system) and the spinal cord.
i.
Signaling between neurons is a very special type of cell – cell signaling.
One thing that specializes them is the type of chemicals that are used for
signaling and these include the neurotransmitters and the neuropeptides
as well as the speed and the specificity of the signal.
ii.
Today we are gonna talk about synaptic signaling, which is a type of
paracrine signaling where the signaling takes place between 2 different
neurons or between a neuron or its target cells and this happens in the
synapse.
iii.
Acetylcholine was the first neurotransmitter to be identified by Otto
Loewi. He isolated Ach from a specific preparation and showed that it
could regulate the activity of the heart. He won the Nobel Prize for the
discovery of Ach.
II.
Outline [S4]
a. First talk about nervous system and kinds of cells that make it up.
b. Ion channels involved in action potential and synaptic signaling.
c. Morphology and function of pre-synaptic and post-synaptic area.
d. How neurotransmitters are made
e. Post-synaptic response and receptor proteins involved
f. Diseases
III.
Review of nervous system and neurotransmission [S5]
a. Two main types of cells comprise the nervous system  neurons and glial cells.
Glial cells glue their neurons together, metabolic support, removing toxins and small
molecules and myelination and immune function.
i.
Synaptic signaling uses neurotransmitters, but it’s a lot more specific
because synapses are regions where neurons are close together, specific
because there are very specific receptors, and synaptic signaling is very
rapid and neurons can communicate with each other in milliseconds.
ii.
Nerve cells are highly polarized cells. They have a cell body, which contains
the nucleus, protein synthetic machinery. This is where the majority of
proteins and mRNA are synthesized.
iii.
It also has 2 regions of specialization: dendritic regions  long thin
processes, which are the info receiving part of a neuron. Other neurons
make contact with these dendrites at the synapse. Typically neurons have a
lot of dendrites. They are highly branched and this is called dendritic
arborization. Dendrites also have dendritic spines  signaling at synaptic
spines is the major place where excitatory transmission takes place between
neurons.
iv.
On the other side is the axon. It’s the info sending part of the neuron.
Typically neurons have 1 axon, but it can branch at the end and produce the
axon terminal.
v.
So the flow of info is from the dendrites or the cell body to the axon.
FUNDAMENTALS 1: 10:00-11:00
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vi.
SCRIBE: KRATIKA PAREEK
PROOF: ANGI GULLARD
PAGE 2 OF 11
Speed of synaptic transmission is determined by myelination. Majority of
neurons in the PNS have a specific insulation called myelin. It speeds up the
conduction of synaptic signaling and also allows for more efficient signaling.
Some of the neurons in the CNS (central nervous system) go through the
white matter. This is where the axons of the brain have their myelin sheaths.
IV.
Central nervous system [S6]
a. There are 2 main parts of the nervous system: CNS = brain and spinal cord and the
PNS = sensory neurons and the projections (axons) from the motor neurons.
i.
PNS is involved in gathering, collecting, and detecting sensory kind of
information such like heat, light, pain, and the axons will then transfer this
info into the spinal cord or the brain. CNS then integrates that info, stores it,
and the brain will decide to generate specific behavior. Behavior is performed
by the motor neurons in the form of muscle contraction.
ii.
There are many different kinds of neurons that make up the different
divisions of the CNS and the PNS and the types of signaling is wellconserved.
b. Talk about how neurons communicate with their target cells, what neurotransmission
is and what are some of the neurotransmitters and how they perform their function.
V.
Different kinds of neurons and their morphology [S7]
a. The 2 major types of neurons in the PNS are sensory neurons and the axons and
projections of motor neurons.
i.
Cell bodies of motor neurons lie in the spinal cord. So the motor neurons are
a part of both the CNS and the PNS.
ii.
The motor neurons project their axons to 2 different types of targets. One is
muscle cells, and they can innervate and form contacts and signals to
skeletal, cardiac, and smooth muscle. Motor neurons can also regulate
glands and so they can control secretions of other cells and they are found in
the PNS.
iii.
So this is info being sent from the brain to the rest of the body.
b. Sensory neurons gather info from different parts of the body and send it to the CNS.
c. Other neurons found in the brain and the spinal cord are called interneurons. There
are many different kinds of these.
i.
They can be found in the cortex, the cerebellum, hippocampus, throughout
the spinal cord.
ii.
They receive info from the sensory and other neurons, integrate this info and
generate behavior by synapsing on motor neurons and allowing for the info
to flow that way.
d. The neurons in the PNS are myelinated because they are often very long and they
have to have this myelination in order to have rapid and efficient conduction.
e. Many of the neurons in the CNS are myelinated, but are not either.
VI.
The conduction properties of nerves [S8]
a. So I’m gonna give an overview of what I am going to talk about today, and this is the
essential core of what you need to know about synaptic transmission.
b. Drawing on the board  neurons use electrical signal called the action potential to
send info to their target cells.
i.
Action potential is a way of depolarization followed by repolarization.
FUNDAMENTALS 1: 10:00-11:00
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THEIBERT
NEUROTRANSMITTERS
ii.
iii.
iv.
v.
vi.
c.
SCRIBE: KRATIKA PAREEK
PROOF: ANGI GULLARD
PAGE 3 OF 11
Action potential travels down the axon. It’s generated at the axon hillock
because this is where the voltage-gated sodium channels are concentrated
and this is what begins the action potential.
Action potential travels down the axon until it arrives at the pre-synaptic
region (before the synaptic region).
When the action potential arrives at the pre synaptic terminal, the electrical
signal gets converted to a chemical signal. This occurs in 2 ways.
First there is an activation of calcium influx into the pre-synaptic terminal.
This signal is sensed by proteins present on vesicles called synaptic
vesicles, which contain high concentrations of neurotransmitters. So you
have pre-packaged neurotransmitters in these vesicles found concentrated in
the pre-synaptic region.
The influx in calcium then instructs these vesicles to fuse with the presynaptic plasma membrane and they release their contents in the region
between the 2 cells called the synapse.
vii.
The synapse is a very small space about 20 nm in diameter. A synaptic
vesicle is about 40-50 nm. It’s very close to the post-synaptic membrane, but
the 2 membranes are not fused. So the signaling that takes place between
these 2 cells has got to occur through neurotransmitters.
viii.
The vesicles fuse and this allows the neurotransmitters to be put into the
synapse. They bind to specific receptors on the pos synaptic cells. These
receptors mediate changes in the postsynaptic cells, which then mediates
the synaptic transmission.
ix.
There are 2 different types of receptors: receptors which directly activate
changes in the electrical properties of neurons, and there are neurons which
are involved in producing 2nd messenger through G-proteins.
x.
This info then can lead to electrical changes in the dendrite, which are
transmitted passively along the dendrites. There can be 1000s of different
inputs at the neuron and at the axon hillock all of these inputs are summed.
Some can be excitatory or inhibitory and if the summation allows for large
enough depolarization this neuron will then fire an action potential.
xi.
So these are the main parts of an action potential that you are going to need
to know.
So I’m going to start talking about action potentials. The resting membrane potential
in most cells is -60 to -70mv. It’s negative on the inside with respect to the outside.
i.
If that membrane potential becomes more positive up to about -50 or -55mv,
and if that cell is an excitable cell i.e. it has voltage-gated ion channels, that
cell will be able to fire an action potential.
ii.
An action potential is an all or nothing wave of depolarization of the plasma
membrane. What happens is when the membrane potential becomes more
positive, it activates an increase in sodium permeability first, followed by an
increase in potassium permeability second.
iii.
These are caused by the specific set of ion channels found at the axon
hillock and also the length of the axon.
iv.
The resting potential changes due to some inputs that the neuron is receiving
that leads to this very large depolarization and the membrane potential goes
up to +30 and then the membrane repolarizes and it actually repolarizes past
the resting potential. This is called hyperpolarization and then the cell goes to
normal.
FUNDAMENTALS 1: 10:00-11:00
9/20/2010
THEIBERT
NEUROTRANSMITTERS
SCRIBE: KRATIKA PAREEK
PROOF: ANGI GULLARD
PAGE 4 OF 11
VII.
Mechanism of action potential [S9]
a. So what is the mechanism that underlies an action potential? It turns out that it is
carried by 2 different types of voltage gated ion channels.
i.
The initial depolarization is by the activity of voltage-gated sodium
channels, which are found in the axonal plasma membrane.
ii.
At rest, the voltage-gated sodium channels are closed. When they hit
threshold to get to about -50 to -55mv, this change in membrane
potential is sensed by specific protein channels within the core of the
channel.
iii.
This leads to the opening of voltage-gated sodium channels. Remember
that the sodium potassium ATPase keeps the concentration of sodium
high outside and low inside.
iv.
So once you open this channel, sodium then flows down its
electrochemical gradient and flows into the cell, and the cell becomes
more and more positive. It becomes even more depolarized.
v.
Eventually this channel becomes inactive and it closes and it stays
closed for a refractory period until the membrane goes to the resting
membrane potential.
b. Now subsequently, there is an activation of voltage-gated potassium channels. The
sodium potassium ATPase keeps the concentration of sodium high inside the cell
and low outside.
i.
So after the depolarization this leads to the activation of voltage potassium;
potassium goes out and membrane repolarizes back to the resting potential.
VIII.
Structure and operation of ion channels [S10]
a. Ion channels are selective.
i.
They only allow specific ions to flow through them. Sodium channel is
specific for sodium. Potassium channel is specific for potassium.
ii.
Potassium channels are slower than the sodium channels and they are said
to be delayed, and that’s why there is an initial depolarization followed by the
repolarization of the membrane.
b. A lot of what we know about these voltage-gated channels was facilitated by the use
of specific toxins, which have been identified to block these channels.
i.
Two different types of toxins are tetrodotoxin from puffer fish and saxitoxin
from amoebas; they have been shown to block the sodium channels.
ii.
The result of this is that because the neurons in their prey are unable to fire
action potentials because their sodium channels are blocked, these cells are
unable to release their neurotransmitters and they cannot perform muscle
contraction and this leads to paralysis of their prey.
iii.
It’s kind of interesting how no specific potassium channel blockers have been
identified from different vertebrate or invertebrate species.
c. Now let’s look at a segment of an axon.
i.
Here is an action potential, which is being conducted by an increase in
sodium permeability and is being carried down the axon looking at time 0.
ii.
If we look at after a millisecond, we see that the action potential has been
carried to the next segment of the axon and now there is influx of sodium,
and this leads to depolarization of the membrane. Subsequently, you get an
activation of potassium channels, and this leads to repolarization and
hyperpolarization.
FUNDAMENTALS 1: 10:00-11:00
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THEIBERT
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SCRIBE: KRATIKA PAREEK
PROOF: ANGI GULLARD
PAGE 5 OF 11
IX.
Looking at the action potential in motion [S11]
a. The action potential only travels in 1 direction along the axon and the reason for this
is because there is a refractory period after which sodium channels are inactivated.
They cannot be opened again until the membrane potential returns to its resting
membrane potential. And this guarantees that the action potential only travels
unidirectionally down to its pre-synaptic membrane.
X.
Myelination: what is it and what it does [S12]
a. Myelin is specific lipid membrane made by Schwann cells in the PNS and by the
oligodendrocytes in the CNS.
i.
These glial cells produce this membrane, which can wrap around its axons
and lead to its insulation.
ii.
This is critical because this insulation allows for very rapid conduction of the
axon, and it is very efficient.
iii.
Neuronal axons are leaky and so ions can leak across the membrane and
insulation prevents the leakiness of these axons.
b. Myelin has been very well characterized. We know all of the lipids and proteins.
i.
There are specific de-myelination diseases like multiple sclerosis where we
make auto-antibodies to myelin proteins and this leads to decrease in myelin
and that can reduce conduction velocity along specific axons. Motor neurons
are very badly affected in multiple sclerosis because they are so long.
XI.
Myelinated nerves have the advantage...[S13]
a. So what does myelin do?
i.
Myelinated nerves can carry action potentials 10x times faster than
unmyelinated nerves.
ii.
This is very critical because the rate of conduction of an action potential is
proportional to the diameter of the neuron. If neuronal axons were not
myelinated, then we would need neurons with large diameters to take the
action potential to the periphery at the rate at which we need them, especially
for things like escape responses.
XII.
How myelinated neurons work? [S14]
a. Myelination creates a problem because you have created a barrier to the flow of ions
across the membrane.
i.
The way that neurons get across this is by having gaps at specific regions in
the neurons. These are called nodes of Ranvier. Here the plasma membrane
has direct access to sodium and potassium ions flowing across the
membrane.
ii.
Because of this reason conduction of action potentials in myelinated axons is
called saltatory.
iii.
What this means is that you have specific regions where there are
concentrated voltage-gated sodium and potassium channels where there is
activation of these channels at these unmyelinated gaps, and sodium and
potassium can flow in and out.
iv.
Then you have a passive flow of sodium and potassium down the axon of
concentrated regions of voltage-gated ion channels, which can then be
activated.
v.
So you have a jumping of action potentials from the nodes of Ranvier.
FUNDAMENTALS 1: 10:00-11:00
9/20/2010
THEIBERT
NEUROTRANSMITTERS
SCRIBE: KRATIKA PAREEK
PROOF: ANGI GULLARD
PAGE 6 OF 11
XIII.
The pre-synaptic area [S15]
a. The action potential is travelling down the neuron. It’s an electrical way. So what is
the purpose of this?
i.
The reason that action potentials are so important is that they will allow
transmission of info from one nerve to its target cell, and the way it does this
is through synaptic transmission.
ii.
I will talk about the pre-synaptic region as the region where transduction
takes place, the synthesis of neurotransmitters in this region, and then the
mechanism of neurotransmitter release.
XIV.
The pre-synaptic area is a very busy...[S17]
a. Pre-synaptic area is part of the axon and this can be viewed morphologically as pre
synaptic to the synaptic region. It’s highly enriched in synaptic vesicles.
b. These pre-synaptic vesicles have to be loaded up with neurotransmitters before they
can be released. They are generated from the early endosome in a cycle, which
allows them to be filled up with neurotransmitters.
c. When the action potential arrives at the pre-synaptic terminal, it activates voltagegated calcium channels in the pre-synaptic membrane.
i.
The voltage-gated calcium channels are activated by the depolarization that
is brought by the action potential.
ii.
In addition to the sodium and potassium gradient, there is also a high
concentration of calcium gradient outside the cell.
iii.
You open up the voltage-gated calcium channel, and calcium flows down its
concentration gradient and into the pre-synaptic neuron.
iv.
Once the calcium gets in there, it stimulates the fusion of synaptic vesicles
with the pre-synaptic plasma membrane.
XV.
Figure showing what she talked about in the previous slide [S18]
XVI.
Arrival at the synapse [S19]
a. Before I talk about what some of the mechanisms are for the vesicles fusing, I wanna
talk about neurotransmitters.
i.
Neurotransmitters are a type of chemical that are specific in synaptic
signaling.
XVII.
The synthesis of neurotransmitters [S20]
a. One of the first characterized neurotransmitters was acetylcholine (Ach)
i.
Ach is made by acetyl CoA and choline, and the enzyme choline acetyl
transferase.
ii.
Acetyl CoA is made in the mitochondria. Choline is pumped into the neuron
by a specific choline transporter, and together in the cytoplasm these two
combine to form Ach.
iii.
Ach is one of the major excitatory neurotransmitters. It’s the main
neurotransmitter in the skeletal muscle.
iv.
It’s made by motor neurons and Ach works on skeletal muscles to induce
contraction.
v.
Once Ach is made it has to be pumped into the synaptic vesicles and there is
Ach transporter, which is present in the synaptic vesicle membrane, which
pumps Ach up its concentration gradient to fill the vesicles with Ach.
FUNDAMENTALS 1: 10:00-11:00
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THEIBERT
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SCRIBE: KRATIKA PAREEK
PROOF: ANGI GULLARD
PAGE 7 OF 11
XVIII.
Diagram of synthesis and storage of Ach [S21]
a. You have formation of Ach in the cytoplasm. Ach will then get selectively taken up
and pumped into the synaptic vesicles.
b. These vesicles are ready to respond to the calcium signal by the voltage gated
calcium channel. These vesicles are pretty symmetrical and contain about 8,00010,000 molecules of Ach.
c. This packet of vesicle is called quantum and release of synaptic vesicles is quantal
because these individual packets of synaptic vesicles will release the
neurotransmitter into the synaptic cleft.
XIX.
The synthesis of neuroephinephrine [S22]
a. The other kind of excitatory neurotransmitter is glutamate, which is one of the
building blocks of proteins.
i.
It’s a major excitatory neurotransmitter found in the brain and the spinal cord.
ii.
The region where the synaptic transmission takes place for glutamate is on
the sub region of the dendrites called the dendritic spine.
b. The major inhibitory neurotransmitter is GABA (gamma amino-butyric acid) used in
the brain and glycine, which is used in the spinal cord.
i.
What we mean by inhibitory is when they bind to the post-synaptic cell that
leads to the inhibition of the cell or the hyperpolarization of the receptor
response.
c. We have modulatory neurotransmitters, which include catecholamine and the
neuropeptides.
i.
Catecholamine includes things like dopamine, epinephrine and
norephinephrine.
ii.
They have tyrosine as their precursor. It’s acted on by tyrosine hydroxylase
to make Dopa. This is often given to people with Parkinson’s disease
because this is a precursor to dopamine.
iii.
Dopa is converted by aromatic amino acid decarboxylase to dopamine.
iv.
Dopamine can then be converted to norepinephrine by the enzyme
dopamine beta hydroxylase.
v.
Investigators use the presence of these different synthetic enzymes in a
neuron to determine what kind of neuron it is.
vi.
Dopaminergic neurons only have TH and the AAAD enzyme because they
only make dopamine.
vii.
In contrast, norepinephrine-specific neurons also contain the dopamine beta
hydroxylase, which converts dopamine to norephinephrine.
viii.
There are only a few neurons that use epinephrine as their neurotransmitter.
But they share the biosynthetic pathway and the final specific
neurotransmitter are neuro-modulatory in their function because they
modulate the activity of neurons.
d. Like Ach there are specific transporters whose job is to transfer these
neurotransmitters into the synaptic vesicles. All these enzymes are found in the
cytoplasm, but the neurotransmitters themselves have to get concentrated into the
synaptic vesicles.
e. For the major excitatory neurotransmitter, glutamate, there is a transporter that
transports glutamate into its synaptic vesicle.
Skipped slide 23.
FUNDAMENTALS 1: 10:00-11:00
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SCRIBE: KRATIKA PAREEK
PROOF: ANGI GULLARD
PAGE 8 OF 11
XX.
Calcium ions induce the transport and fusion...[S24]
a. We know that calcium influx has occurred into the pre-synaptic vesicle. How does
this calcium influx lead to synaptic vesicle fusion?
b. There are specific proteins that have been identified on the both the synaptic vesicle
membranes as well as the pre-synaptic membrane, which facilitate the fusion of
these vesicles to the plasma membrane.
XXI.
Figure [S25]
a. Here is the figure that depicts what I said earlier. There proteins were originally
identified in yeasts.
i.
They form this protein-protein interaction and they bring the vesicle into very
close proximity with the plasma membrane and dehydrate to get rid of the
water molecules that are surrounding these two lipid bilayers.
ii.
Once you bring the two membranes close together, the lipids will
spontaneously fuse.
b. This is under calcium-dependent regulation and the calcium sensor is a protein called
synapti-tagnan (I don’t know how to spell it).
i.
It enters into the protein-protein interaction and it prevents vesicle fusion in
the absence of calcium.
ii.
When calcium levels increase, it removes the inhibition of synaptic-tagnan
allowing these proteins to interact with each other and bring the synaptic
vesicles close to the plasma membrane and allowing for fusion.
c. So this is a type of regulated exocytosis.
i.
Once the synaptic vesicles have fused with the plasma membrane they have
to be recovered otherwise you would just expand this plasma membrane presynaptically.
ii.
So you need a balance of endocytosis of this membrane and there are
different proteins involved in the endocytic pathway, which allow for the
recovery of synaptic vesicle protein components.
iii.
Once the vesicles go back inside the cell, they fuse with the early endosome
and you can regenerate synaptic vesicles from this region.
XXII.
Neurotransmitters are simple, small molecules [S27]
a. There are different kinds of neurotransmitters.
i.
The cholinergic neurons, motor neurons, and few other cholinergic neurons
throughout the brain.
ii.
When we talk about a neuron being cholinergic we talk about the kind of
neurotransmitter it releases. That neuron can have many different inputs and
can receive many different kinds of info.
iii.
Catecholamine including dopamine and norephinephrine are found
throughout the brain. They are very important in regulating things like mood
and behavior, cognitive and executive function
iv.
Amino acid derivatives include glycine, glutamate, and GABA. These are the
transmitters that mediate excitatory and inhibitory transmission.
v.
Epinephrine is found throughout the body. It can also act on neurons at the
periphery and lead to vasoconstriction as well as the neuro-modulators
including the endorphins and other peptides.
b. In general, a neuron will only synthesize a specific type of small molecule transmitter,
but it can also make specific neuropeptide transmitters.
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PROOF: ANGI GULLARD
PAGE 9 OF 11
XXIII.
General list that investigators have come up with [S29]
a. Neuro pharmacologists and neuro chemists, since Ach was identified, have come up
with specific criteria to identify a molecule as being a neurotransmitter.
b. The criterion is that it has to be at the synapse. You have to be able to make it.
c. It has to be released from synaptic vesicles
d. It has to produce an effect in the target neuron and you should be able to mimic that
effect by exogenously applying that neurotransmitter.
e. The effect it produces should be directly proportional to the amount of
neurotransmitter released.
f. There have to be mechanisms to remove or inactivate the neurotransmitter.
g. Initially this is how we identified and classified neurotransmitters.
h. It has become a gray area because there are some molecules that can be released
that are not packaged into vesicles. These include some lipophilic molecules like
small free radical gases, nitric oxide. They have many of these properties that they
can modulate neurons and their release is stimulated, but they are not packaged into
synaptic vesicles.
XXIV.
Arrival at the synapse [S30]
a. One of the main criteria that has to be met by neurotransmitters is that it has to be
inactivated.
b. So another property of synaptic signaling, which distinguishes it from other endocrine
or paracrine signaling is that not only it is very rapid, but it is also very transient.
c. The reason for this is that at the synapse there is both active and passive mechanism
to inactivate neurotransmitter.
i.
Passive mechanism is that a lot of neurotransmitter just diffuses out of the
synaptic region.
ii.
But some neurotransmitters are actively degraded and there are enzymes
that actively degrade and remove these. For example, Ach is removed by
Ach-esterase at the neuromuscular junction, which degrades it into choline
and acetate. Choline can be retaken back into the motor neuron.
d. Other neurotransmitters like glutamate and dopamine have specific transporters
found on the pre-synaptic plasma membrane as well as the glial plasma membrane
on the glial cells that are found nearby.
i.
These are selective uptake mechanisms that transport the molecule back
into the pre-synaptic neuron or into the glial cells.
ii.
These are things like glutamate transporter and the dopamine transporter.
iii.
Many of these transporters are important in psychiatry because things like
serotonin and dopamine or non-adrenergic transporters are the targets of
many drugs, which are used for treating depression.
XXV.
A quick review and lead in to what occurs at the post synapse [S31]
a. Once you have the release of neurotransmitter in the synapse that neurotransmitter
before it gets degraded or taken back up better do something and what it does is it
interacts with receptors on the post-synaptic membrane and generates a specific
response.
XXVI.
Post synaptic receptor proteins [S33]
a. There are 2 types of receptors, which are involved in regulating the response, and
these are called the transmitter gated ion or ligand gated ion channel, which mediate
vast synaptic transmission.
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PAGE 10 OF 11
i.
Ach at the neuromuscular junction and the glutamate receptors on dendritic
spines are ligand-gated ion channels.
ii.
They bind the neurotransmitter. They are themselves ion channels and when
they open up they allow either sodium or chloride ions to flow down their
concentration gradient and directly lead to a change in the membrane
potential of the post-synaptic cell.
b. The other type of receptors is called metabatropic receptors, because they are
involved in regulating metabolism.
i.
They use G-proteins and 2nd messengers.
ii.
The targets for these 2nd messengers are ion channels themselves.
iii.
So indirectly, these can lead to changes in the electrical properties of the
post-synaptic neurons using these G-proteins and 2nd messenger coupled
pathways.
XXVII. If we consider Ach, it will bind..[S34]
a. So this is an Ach receptor. Sub-type is called nicotinic receptor and it can modulate
its properties. It’s an ion channel and it’s found on the post-synaptic cell.
i.
One of the best characterized nicotinic Ach receptors are found at the
neuromuscular junction and they are found the muscle cells.
ii.
Ach binds to these receptors. It opens up the ion channels and sodium flows
into the post synaptic membrane and this can lead to depolarization of the
muscle membrane and activate the actin-myosin machinery and lead to
muscle contraction.
b. Ach receptor is a non-selective cation channel.
i.
So sodium flows down its concentration gradient first, but it will also allow
potassium to allow to flow out of the postsynaptic cell. And it also allows
calcium to flow in as well.
ii.
The concentration of sodium in extracellular region is more than calcium, so
sodium is the major conducting ion for this channel.
c. Other types of ion channels are similar to nicotinic Ach receptor. Normally it binds
Ach and nicotine is just used to distinguish its subtype.
d. Other ligand gated ion channels bind to the ligand on the extracellular, opens the
channel and allows for ions to flow in.
Skipped slide 35.
XXVIII. Muscarinic Ach receptors [S36]
a. The other type of receptor is muscarinic Ach receptor.
i.
This is a G-protein coupled receptor (GPCR).
ii.
It binds Ach on the outside, activates a specific G-protein.
iii.
One of the major targets for G-proteins is ion channels. In this case, a
specific potassium channel. When this potassium channel is activated,
potassium will flow out of the cell and lead to a hyperpolarization.
iv.
Going back to the first slide, when Loewi originally identified Ach, he found
that it slowed down the heart rate. Now we have identified the mechanism
that the effect of Ach is through GPCR to slow the heart rate.
XXIX.
Parkinson’s disease [S37]
a. So now I want to talk a little bit about disease mechanism.
b. Parkinson’s disease is a disease in which we use L-Dopa. Another agent is
bromocriptine.
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THEIBERT
NEUROTRANSMITTERS
i.
ii.
iii.
XXX.
In this disease you lose a specific subset of neurons in a region called the
substantia nigra.
In the substantia nigra are dopaminergic neurons that project to many places
throughout the brain. One of the places it projects to is the caudate nucleus
and then the caudate can regulate specific motor behaviors.
Bromocriptine is a type of dopamine receptor agonist. It stimulates the
dopamine receptors post-synaptically. So together with L-Dopa,
bromocriptine is an important neuro-pharmacological agent to treat diseases.
What is important to know [S38]
Questions that Dr. Whikehart thinks we should know.
[END 54:34 mins]
SCRIBE: KRATIKA PAREEK
PROOF: ANGI GULLARD
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