Neuroscience - Postsynaptic Neuron

Choi - B (1-1:50pm)

Okay. It's a Friday so let's just get it done and maybe we can get out of here. But -- yesterday I was discussing,
among other things, the mechanisms involved in the release of transmitters from the presynaptic neuron at a
synapse. And in the process of releasing the transmitters you do certain things that require eventual recycling to
restore homeostasis. You, in at least some of the vesicles that release their transmitter, you've added a certain
amount of lipid to the cell membrane and that has to be recycled and we discussed that. In the process of releasing
the transmitter youve allowed calcium to be moved from the extracellular fluid into the cytoplasm to the
presynaptic nerve. And we already discussed how you get that back out. If anything you do in a presynaptic neuron
is you release transmitter and the transmitter then binds to some molecule on the post synaptic cell. And it binds
reversibly, it attaches, it detaches. Eventually you got to get rid of that transmitter. And everything I said up to now
is more or less independent of what that transmitter is. You have an presynaptic neuron, you have an action potential
and you release transmitter into the extra cellular space surrounding the presynaptic neuron. Now generally there's a
close apposition between the presynaptic neuron and the postsynaptic neuron so that the transmitter has a good
chance of crossing the space between the Synaptic gap or Synaptic cleft. And actually reaching the post Synaptic
cell. But how small that cleft or space between -- in the synapse between the presynaptic and the post synaptic cell
is, correlates with the type of transmitter you are dealing with. And then you have the problem of once the
transmitter is released in that space of getting rid of it so everything is reset to the way that everything had to been to
the way it had been before and you're ready for the next action potential to come along and release another batch of
transmitter into that space. You dont want the presynaptic cell to say "I don't need that I got all that I need already."
So what happens here is this, the transmitter is released into the synaptic cleft it has to sort of wander across the
distance and the distance can be very small or a little larger or even larger still. Generally its relatively small on a
cosmic scale of things but it varies depending on the nature of the transmitter. At some point the transmitter
encounters the post synaptic cell which has on it some receptors. That are capable of specifically binding that
transmitter. And what happens there is the transmitter plus the receptor reversibly bind to form a transmitter
receptor complex and the binding or attachment of the transmitter molecule to the receptor molecule causes the
receptor molecule to go undergo some sort of a change in its configuration in its structure. So we'll just indicate that
with an asterisk. And then this leads to a whole circus of things that could happen depending on what the nature of
that receptor is and the transmitter that bound to it. What right here is the first step. The transmitter has to reach
the receptor which means crossing the space between the cells. And then that the problem of recycling or at least

Neuroscience - Postsynaptic Neuron

Choi - B (1-1:50pm)

getting rid of, not necessarily be recycling or in the long run your whole body it is. You have to get rid of the
transmitter so it's no longer in that space so when the next action potential releases another bunch of vesicles full of
transmitter the receptors are empty and waiting for that transmitter. And basically you have for discussing this you
have three different classes or groups of transmitters that might be involve and the character of -- the category,
which one of these three categories of transmitter determines two of those things, the width of the space between the
cells and the mechanism of deposable or illumination of the transmitter or of that space. Category number 1, is
acetylcholine is which is unique. A presynaptic neuron synthesizes acetylcholine from acetyl coenzymeA plus
choline and choline is a small molecule. It's basically ethanolamine that is you have two carbons, you have a
hydroxy here, thats the ethanol and then you have an amine. NH2 if you like. And this gets methylated on the
ammonia- on the nitrogen. So first you replace one of the hydrogens with the methyl group then you replace another
one of these with a methyl group. And the key step is adding on a third methyl group. In order for nitrogen to be
connected to four different things. Think back to your first -- earliest organic chemistry. It has to get rid of an
electron. So it sort of -- its electrons shells look like carbon. And to do that you get rid of one of electron it takes on
a positive charge. Now this is referred to as a quaternary nitrogen or a quaternary amine. These are hard to make.
You have to do a lot of work to create this charge. And this compound here is referred to as choline. Choline is
expensive, takes a lot of work for the cells to make it. But acetyl CoA plus choline is synthesized into acetylcholine
generally written capital A capital C small h. And that's the transmitter that's released in the first category of cells of
presynaptic cells. And the way in which the action of acetylcholine is terminated in one of these synapses is that
theres an enzyme, acetylcholinesterase, which breaks the ester bond between the acetyl and the choline,
cholinesterase with an e. And it breaks acetylcholine into acetate plus choline. It's a very strong enzyme, a very
powerful, very active enzyme its present in the synaptic - well not in the synaptic cleft. It's actually present bound to
the membrane of the postsynaptic cell. So it's right next to the receptors. The receptors are sort of interleafed with
the acetylcholinesterase enzyme. So as soon as you have the acetylcholine released and it binds to a receptor, this is
a reversible binding when it separates perhaps, the acetylcholine is attacked by acted on by one of these enzyme
molecules and destroyed. So very quickly acetylcholine acts very quickly, two reasons one of which is its not
around very long so it can't linger because its destroyed by the enzyme, but second the acetylcholine synapses are
narrow have a narrow (Cuts off)

Neuroscience - Postsynaptic Neuron

Choi - B (1-1:50pm)

Okay, is it working? I can't tell. Already now, I'll stick it in my pocket. Clip it on and now I've got nothing to do
with my hands. The cleft, the space acetylcholine mediated synapse is referred to as cholinergic, in case you come
across that word, are very narrow. So almost as soon acetylcholine is released from the presynaptic neuron it
reaches the postsynaptic cell. Very small space for it to cross. And once it does that it strikes either a receptor or an
acetylcholinesterase molecule. In which case its destroyed. And once that happens you gotten effectively rid of the
acetylcholine. The activity of these enzymes, the acetylcholinesterase, is such that about more than half maybe even
two thirds of the molecules of acetylcholine that are released from the presynaptic membrane, presynaptic cell are
destroyed by the acetylcholinesterase before they even see a receptor. So this is a very active enzyme that very
quickly destroys the low battery for the other one, battery went dead on the big mic. Now as I said before choline
molecules are hard to make, hard to synthesize so these are recycled and it is a very efficient recycling system.
About 85 percent of the choline that is produced by breaking down the acetylcholine is remade - is taken back into
the presynaptic cell where it's used to make new acetylcholine. So theres cells that release acetylcholine have a
choline transporter that takes the choline part back into the cell. Okay. That's the first category. Second category of
transmitters are the group that are called the catecholamine these include; norepinephrine abbreviated NE,
epinephrine or EPI, dopamine, and also one noncatecholamine its structural referred to as an indoleamine,
serotonin. Thank you.
Okay. What happens when these compounds are released as transmitters is first of all they are not as fast acting as
acetylcholine and one of the reasons is the cleft between the cells is slightly larger, so it takes a little time for the
molecules and transmitter to cross the space and reach receptors on the post synaptic cell. Once they've done
whatever it is they've done, how are they moved from the synaptic cleft from the space between the cells, is a
process known as reuptake. Its an awkward word formation probably coined by someone whose first language was
German. Reuptake is that it's taken back to the cell that released it. And what you have in this situation is this you
have a nerve ending you have your transmitter filled vesicle that releases its transmitter and it hits the membrane
right? That's an epinephrine. There's a two stage heres an empty vesicle from ... whatever. The molecules are
pumped transported by a very specific transporter back into the cytoplasm. This is called reuptake one. And from
the cytoplasm there's another transporter molecule that transports dopamine or more epinephrine whatever, into the
vesicle and that's called reuptake two. It's a two stage operation. And it's very -- there are clinical and
pharmacalogical factors that take advantage of the fact that its two stage uptake. Because in these cells, in the

Neuroscience - Postsynaptic Neuron

Choi - B (1-1:50pm)

cytoplasm. Theres an enzyme monoamineoxidase or MAL that destroys these transmitter molecules. All of these
are mono amines to be sure, that there is one amino group. And it oxidizes and thereby destroys the transmitter
molecules. So what happens is the reuptake into the cytoplasm -- there are two different pathways here, it can then
go into the vesicle or it can then be destroyed once it's in the cytoplasm. So it's the world's most efficient
mechanism. Long ago we discovered a group of drugs that inhibit the monoamineoxidase and make the reuptake
more efficient because everything that gets taken up into the cell gets into the vesicle. It's not destroyed in the
cytoplasm because you've inhibited the monoamineoxidase. And these MAL inhibitors were used as
anti-depressants, among other things. But you're beginning this next year in pharmacology. I assume you will. But
the point is they are not used now because there are too many side effects. But the point I'm making is that in the
case of these transmitters, the action of the transmitter is ended. The transmitter is removed from the synaptic cleft
by the process of reuptake. The third group of transmitters is all the rest. These include amino acids. Including
modified amino acids. One of which is very important transmitter gamma amino butyric acid or GABA. Purines
such as ATP. Sometimes peptide. Two, three, four molecules, three or four amino acid peptides. They're not
proteins, they're too small. And an assortment of other compounds that sometimes appear as transmitters. These
don't have any specific destruction mechanism. They don't have any specific transport mechanism. What they have
is the fairly wide on the scale of very narrow, a little wider, very wide synaptic space between the pre and post
synaptic cells and as a result of that the beginning of their action on the post synaptic cell is slow but it lasts longer.
It lasts a hundred milliseconds as opposed to a millisecond in the case of the acetylcholine. And the reason for that
is there's no active way of getting rid of them. What you have is essentially dilution to the whole body extra cellular
fluid. If you put a drop of ink into a bucket of water gradually defuses away and finally it concentration is so low
that it don't have any effect. And anybody who mentions homeopathic medicine is going to be failed in the course.
And basically what you have is just diffusion until it's too dilute to significantly activate any of your receptor
molecules. But what happens here, once you got this part of the sequence here. You have a transmitter attached at
least temporarily to a receptor. And the receptors changes its configuration or its confirmation. For the most part
these receptors are glycoproteins of various of sorts. What happens here? What's the next step? Well, it depends on
which of two types of synapse you are dealing with. There are synapses that are referred to as ionotropic. And there
are synapses are referred to as metabotropic. And the ionotropic ones act through adjusting permeability of
postsynaptic membranes to ions. The metabotropic case the transmitter acts by adjusting the metabolism, that is of

Neuroscience - Postsynaptic Neuron

Choi - B (1-1:50pm)

the post synaptic cell this is it activates or inactivates the enzyme in the postsynaptic cell and that lead to
consequences. We'll go through these separately. In an ionotropic synapse, what happens when the receptor it is
struck by or attaches to a transmitter or the transmitter, strictly speaking, attaches to the receptor because the
receptor isn't going anywhere. In most cases the receptor is part of a molecular complex that includes a channel
through the post synaptic membrane for some particular ion. And binding the transmitter to the receptor changes the
configuration through the receptor and the channel so that the permeability of a particular ion and the post synaptic
cell is altered, either it increases or decreases. So the matter of fact is that, I taught this class room from 9 to 10 and
now you guys. A Week from Thursday, I have an 8 to 6 day that I'm not looking forward to it because it involves
two different courses. And the double teaching. A change in the configuration of the receptor-channel will increase
or decrease the permeability to an ion and then that in turn will change the membrane potential in the postsynaptic
cell. And why is that important? Well, one of the things the nervous system does when their synapses from neuron
to neuron is sort of integrate or average all the inputs on to a postsynaptic neuron. In most cases, well in one case
synapses are from many cells on to a postsynaptic cells. You have many presynaptic cells synapsing onto
postsynaptic cells which will have a variety of receptors and will receive a variety of transmitters and each will
cause a permeability change in that post synaptic cell. Some of them will depolarize it. Some will repolarize it. Or
something else that's a little inbetween. But -- and the whole question then is does the second cell if it's a neuron,
initiate an action potential. Which is a yes or no, all or none process. So what happens is any inputs, synaptic input,
to a postsynaptic neuron or skeletal muscle fiber or smooth muscle fiber or cardiac muscle fiber that's ionotropic.
You need to change, we'll use a delta for a change, in some permeability, which will lead to a change in the
membrane potential. You could -- if you increase sodium ion permeability for example. It will tend to shift the
membrane potential closer to the sodium Nersts potential of plus 60. It depolarizes cell. And it makes for likely that
that cell will eventually reach minus 55. 'Cause if your below -- more negative than minus 55 and you bring it up to
plus 60 there's a good chance you'll reach minus 55 or a greater chance than that was better. So this is considered an
excitatory event. And generally these --this sort of thing is referred to as an EPSP which stands for excitatory post
synaptic potential. Which is a terminology that dates back to the 1940s. 1930s even when they very sloppily use the
word potential to indicate either a membrane potential or a change in the membrane potential. Its very poor naming
but it stuck. It is an excitatory post synaptic potential. If you increase PK on the other hand this will bring is the
membrane potential closer to minus 80 something. And make it less likely that the cell will depolarize to minus 55.

Neuroscience - Postsynaptic Neuron

Choi - B (1-1:50pm)

'Course you were starting at minus 70 thereby making it more negative, so you're getting it away from minus 55.
And that's considered inhibition 'cause it makes it less likely to produce an action potential in that cell and that's
referred to as an IPSP. This change can be either an increase or decrease in permeability. Suppose you have a
decrease in PK as your postsynaptic effect. If you decrease the PK then this makes the sodium contribution to the
equation that much bigger. So all intents and purposes decreasing PK is the same as increasing all the other
permeabilities around. So effectively a decrease in this permeability will have the opposite effect of an increase.
Decreasing the permeability to an ion will have an opposite effect that an increase in that permeability would have.
So this is actually excitatory. And analogously a decrease in P sodium which will be less pressure moving it
towards plus 60 would have the opposite effect of this which is always a depolarization so this would be an IPSP.
Now there's one more ion that I have to bring to your attention. And that is this, let's write the Goldman equation.
And now you can add additional terms further ions that might be permeability and have their permeabilities
changed. And one of these is chloride. Let's look at the equation for the Nersts potential for chloride. We' going to
do minus 60. But where did the 60 come from? Remember the conversion from natural logs to logs to the base 10
and the 60 came from RT over Z times F. The faraday constant right? That's the Nersts equation. Except for
chloride, Z is minus 1. So minus and this minus becomes plus. RT over F, in over out. But we don't want to see a
plus sign here because we want a term more like this is the potassium Nersts potential alone if you eliminated the
sodium part. And this is the sodium Nersts potential equation part if you eliminate the potassium part. You want
this to look like minus 60 log of something. So what we'll do in the case of chloride, we'll write minus 60 log of
concentration of chloride out over in. 'Cause turning this fraction upside down changes the sign of the logarithm.
Remember the logarithm of reciprocal is minus the logarithm of the original. So this becomes P chloride, chloride
out, P chloride in. And you see it gets more complicated when you have bivalent ions like calcium. Im not going to
- it gets really complicated 'cause you have square roots and things. But with monovalent ions, you can continue the
same format except with negative ions you have out over in. All right, and if you go through the whole calculation
of what's the Nersts for chloride given the concentrations you find that E chloride is something like minus 65
millivolts. So if you increase P chloride it will tend to shift the membrane potential towards minus 65. Is that
excitatory or inhibitory? Well if the membrane potential minus 70 it's a depolarization but it's not an excitatory
event. Because what you're doing is youre going towards minus 65 you're making it harder for a membrane
potential to go beyond minus 65 up towards minus 55. So increasing chloride permeability is an IPSP. The reason I

Neuroscience - Postsynaptic Neuron

Choi - B (1-1:50pm)

go out of my way to mention this is that when you will find that chloride -- that one of the major inhibitory neural
transmitters is something I listed before GABA, gamma amino butyric acid. And GABA increases chloride
permeability and cells that have receptors. And it's an inhibitory transmitters, it produces IPSPs. All right, so that's
the sort of thing that going on with the ionotropic synapses. What about metabotropic? Yes.
Student: When you depolarize doesn't that increase the permeability of sodium?
Slightly, yes. But the overall effect -- but not significantly as soon as you're below minus 55. The increase in
sodium permeability only really begins to get significant when you reach that threshold.
Okay. Metabotropic synapses activate an enzyme. And the enzyme then increases or decreases synthesis of some
compound. How does that work. Now you have a the receptor -- now let's draw part of the cell's surface. Here's the
cell membrane. And you have on the outside of the membrane a receptor. It might extend to the inside surface but
it has to be on the outside or else the transmitter couldn't find it. You have the transmitter plus the receptor forming
a transmitter-receptor complex which changes the conformation of that receptor. Which the transmitter-receptor
complex then floats along the surface of the cell -- on the outer surface of the cell membrane in a fluid mosaic that
you left on the ocean. And eventually it might reach a G protein. And G protein in its inactive state -- well nothing
in particular is going on is almost transmembrane but it definitely reaches the inner surface. And it has a GDP
attached to it. If we look at the G protein, G protein and this is the cytoplasm and this is membrane and this is
outside. The G protein is made up of three components, there's an alpha unit and beta and gamma subunits. And the
alpha subunit is the one that has a GDP attached to it. This is an inactive G protein. When the receptor comes along
with its -- in its inactivated form and then bumps into it brings about a conformational change in the alpha subunit of
the G protein which has two effects, or three effects depending on how you count. You convert the alpha to some
activated form. That activated form first separates the alpha unit from the beta and gamma subunits. So now it's
separate. It also loses its affinity for GDP. So the GDP separates out. It disassociates the GDP that it had. Because
in altering this into the active form it now has an affinity, a desire to bind to GTP. So now its bound -- picks up a
GTP. So we have an alpha star, the activated alpha subunit of the G protein with a GTP in the cytoplasm attached to
it. And that floats around in your little ocean. The fluid mosaic of the cell membrane. And eventually the alpha
star -- lets enlarge this a bit, you have your alpha star with the GTP attached to it. Wanders along until it meets an
enzyme. First on the cytoplasmic side. And it turns on the enzyme. So the enzyme that had been not doing

Neuroscience - Postsynaptic Neuron

Choi - B (1-1:50pm)

anything now is enzyme star. Its activated and it starts catalyzing some reaction. And what it generally does is it
leads to the synthesis of something that's referred to as a second messenger inside the cell. There are a large number
of second messengers that form inside various cells and various parts of the body. But the two most common and
best known are these, of second messenger systems; One is the enzyme is adenylcyclase. This is the enzyme E star
and it catalyzes the reaction of ATP into a cyclic AMP plus -- splitting off a diphosphate. And the cyclic AMP is a
second messenger in many systems. It stimulates cardiac muscle to contract. It stimulates smooth muscle to relax.
It stimulates certain secretory systems, such as salivary glands to secrete certain things. It acts on a whole bunch of
glands type things to promote secretion. And what terminates this whole process by the way is the alpha star with
the GTP lasts as long as that GTP does, but eventually it's going to encounter an intracellular GTPase enzyme which
separates into GDP plus phosphate. And once that happens and this is now GDP the alpha goes into its unactivated
form and reattaches to a beta and gamma for what it's worth. The other very widely found item, and you're going to
see these again when we discuss the autonomic system later in this course is this, within -- among the lipids in your
cell membranes there are fatty acids, there's cholesterol, anything that's lipid or lipid soluble will be found there.
One of the things that found in the membrane and remember membranes are constructed off lipids with a
hydrophilic end so that you find the cell membrane this way. That's hydrophillic this is hydrophobic lipid, two
layers, the whole thing. One of the lipids that's found is something called phosphatidyl glycerol. Oh,
phosphatidylglycerol sorry, phosphatidylinositol. This phosphate. The structure is simply this, that's a glycerol three
carbon thing which has a fatty acid attached to this carbon and a fatty acid attached to this carbon and on this third
carbon what you have is a phosphate group and inositol. With two more phosphates attached to it. This is generally
written PIP2. This is an inositol bisphosphate because there are 2 phosphates attached to the inositol, phosphatidyl,
Y-L, indicates that there is a phosphate linkage to the rest of this molecule. What happens in the membrane in
response to the transmitter as appropriate is that the activated alpha subunit with the GTP attached turns on an
enzyme which is a phospholipase C, or PLC. And phospholipase C essentially hydrolyzes this bond here. So what
does that leave you with? You are left with -- this is a hydroxy now, hydrolyze means that you insert a water
molecule basically. So -- and you had an oxygen linker there. So this is a hydroxy attached to a glycerol with two
fatty acids. Two acids diacyl. So this is referred to as two diacyl glycerol. Where would you find this molecule
after its formed? This part is going to be in the lipid part of the membrane. This hydroxy group it going to keep it
near water and this is found as part of the cell membrane but with the hydroxy on the cytoplasmic side of the

Neuroscience - Postsynaptic Neuron

Choi - B (1-1:50pm)

membrane poking into the cytoplasm. This is a sugar, an acetyl is a sugar, a five carbon sugar. With three
phosphate groups added on you can't get more water soluble than that. So this is released in this bond that's
hydrolyzed. This is released into the cytoplasm. And that's where it stays because there is not a chance in hell that
that's going to cross this membrane and get out of the cell. So this compound which is now inositol with three
phosphates on it. Inositol trisphosphate or IP3 remains in the cytoplasm. Now it's interesting these have two
vaguely parallel functions. The diacyl glycerol usually abbreviated DAG travels around the cell membrane and
whenever it sees a calcium channel on a cell membrane it opens that channel so it allows calcium to come in from
the outside. The IP3 floats around the cytoplasm whenever it comes across from cellular structure that has calcium
bound to it. Some smooth calcium smooth endoplasmic reticulum structures perhaps, it releases the calcium into the
cytoplasm. So by two different mechanisms by who different sources both of these second messengers
activate -- increase the contraction of calcium in the cytoplasm. And this can cause a muscle to contract you'll be
getting into that the week after that in basic tissue I guess. And you've got essentially two second messengers that
have similar things. There are other second messengers that can be formed but I'm not going to go into whole
catalogs especially since I went over time. So there you have it. All right, have a good weekend.