Professor Mark Saltzman:
Good morning.
So, this is kind of a
transition week.
We've been talking about more
basic, more biological subjects.
Starting this week we're going
to sort of mix physiology and
Biomedical Engineering,
and that's going to start sort
of this week and next.
The topic for this week is self
communication:
how mechanisms that cells
within a complex organism use to
communicate with each other at
short distances or long
distances.
Then we're going to talk about
two physiological systems just
briefly, where cell
communication sort of dominates
the behavior of the organ.
That's in the immune system and
in the nervous system.
This will lead us into a
discussion of sort of
bioengineering of the immune
system, in particular,
and we're going to talk next
week about vaccines.
This will be the first real
example where we've talked about
the physiology of an organ
system together with engineering
approaches to modulate that
organ,
and that will continue
throughout the semester.
You'll notice that the chapters
because of this go out of
sequence, so we're reading
Chapter 6 this week and next
week we'll read parts of
Chapters 14 and 15,
that's because the book has a
different kind of organization.
It talks about the basics,
then it talks about physiology
in the second part,
and then it talks about
Biomedical Engineering
separately.
But we're going to in class
treat the physiology and the
Biomedical Engineering together.
Any questions about that,
or that makes some sense?
Cell communication and
immunology is what we're going
to - is the topic for this week.
I don't need to say too much
probably about why cells need to
communicate with each other but
this is a schematic version.
One way to draw sort of a
schematic diagram of the
operation of the human body
where it shows separated organ
systems and tries to show them
in context.
The respiratory system,
for example,
the renal system,
the digestive system,
these are examples - three
examples of organ systems that
contact the external
environment.
We've talked about the
interesting way in which the
digestive system contacts the
external environment.
Depending on what you call
external and internal
environment, this path that I'm
tracing here,
deep within your digestive
system, is really directly
connected to the outside world
through both ends.
Of course when molecules
get absorbed through the
intestinal tract they become
part of your internal
environment.
We've talked about one the main
concepts in physiology being
homeostasis, that is 'how do you
maintain a constant internal
environment?
We need to have conditions
internally that are relatively
constant in terms of
temperature,
and pH, and chemical
composition in order for us to
thrive.
In order for life to proceed,
you need to maintain a constant
internal environment.
That's achieved - in fact
that's the main goal of many of
these organ systems,
right?
The main goal of the
respiratory system is to bring
fresh in so that you can extract
oxygen from it,
and blow used air out so that
you can rid of carbon dioxide
which is the end product of
carbon metabolism inside our
bodies.
The respiratory system plays an
important role in maintaining
our internal environment at the
proper level of oxygen,
by bringing the right amount
in.
You regulate your breathing
rate in order to accomplish that
and we'll talk about this in a
couple of weeks.
The renal system has an
equally important function in
that way, in maintaining your
water balance.
The amount of water that you
need to have the optimal sort of
concentrations of things is
determined by how much urine
your kidneys produce and how
much they excrete each day.
In addition,
the kidney controls the
composition of your body of many
important ions,
sodium bicarbonate which is
important in pH balance,
potassium.
By determining how many of
those molecules to hold onto,
how many to keep in the body,
how many to release determines
the internal composition with
regard to that ion.
The digestive system,
of course, is responsible for
bringing in sort of fresh
nutrients,
fresh substrates for cellular
metabolism, fresh quantities of
amino acids, and nucleotides,
and the things that we can't
generate internally.
So, these are all involved with
our ability to maintain
homeostasis by exchanging
materials with the external
environment.
There are some organ
systems that are totally
internal.
The circulatory system which
we'll talk about in a couple of
weeks, the heart,
the blood vessels,
and the blood work together to
form a totally internal
function.
There's no point where the
circulatory system crosses the
boundary between being inside
you and outside of you,
it's totally internal.
Its role is to move molecules
around in the body so that
they're available to cells
everywhere within your body
regardless of how close they are
to your skin,
and we'll talk about that.
The nervous system,
the endocrine system which
we'll start talking about a
little bit today is the system
that's responsible for sending
signals back and forth between
tissues of your body.
The nervous system does the
same thing in a different way.
These two systems which are
shown in the core of this
diagram really are responsible
for regulating and exchanging
information between the other
organ systems.
How do your lungs know what
your heart is doing?
How do your kidneys know what
the status is of inside your
blood, for example?
They know that because they
receive signals from the
endocrine system and the nervous
system.
These are primarily
communication systems which act
to allow your other organ
systems to work in concert.
We're going to talk about
the mechanisms by which these
work as well.
Now there's something very
wrong about this diagram,
in that it's showing these
functions as sort of centralized
in the core,
and of course that's not how
your body is organized.
It's not that all these layers
are wrapped around the nervous
system and the endocrine system.
These systems are dispersed
throughout your body and their
dispersal is important,
and so we'll talk about that as
well.
Take a step way back and
think about what's the basic
mechanism by which cells receive
signals.
It turns out that cells receive
signals or information from the
rest of the body in a variety of
ways,
but there's one way in
particular that's a very useful
way for thinking about how cells
receive most information.
It's shown schematically on
this diagram here.
On the side over here shows a
cell membrane and so this is
outside the cell above it,
and this is inside the cell
below, and this is the lipid
bilayer that separates the
outside of the cell from the
inside of the cell.
I've already mentioned many
times that the lipid bilayer,
the cell membrane,
isn't just a lipid bilayer.
That there are other molecules
in the lipid bilayer and they're
important for cells getting
information or getting molecules
from outside.
We've talked about one
class of molecules,
they're transporters that move
molecules from inside to
outside,
or outside to in,
that wouldn't ordinarily be
transported through a cell
membrane.
Glucose is a great example of
that and we're going to come
back to that a little bit later
in the lecture.
If a cell membrane was indeed
just a lipid bilayer,
then glucose could never enter
the cell because it can't
permeate through cell membranes.
Glucose has to get into cells,
that's the main source of
energy source that cells use,
metabolism of glucose.
It does so because there are
some molecules in the surface of
the membrane that allow glucose
to move in and out.
Those are called glucose
transporters.
There's another whole
family of molecules that sit in
the surface.
They're not responsible
necessarily for moving molecules
inside and out,
but they sit at the outside of
the cell and they wait for
signals.
When they receive the signal
they make - they change in a
very specific way and the cell
can recognize this change that's
occurred at the cell surface.
That general class of molecules
is called receptors and its
shown here just as a block of
material living in the cell
membrane.
We're going to talk about
different classes of receptors
in just a minute.
For now, just picture it in
this simple way as a molecule,
usually a protein,
that's embedded in the cell
membrane and many receptors have
a part of them that is
extracellular.
They go across the membrane -
this is the trans-membrane part
of the receptor that's going
across the membrane.
Then there's a part that's
inside the cell sticking down
into the cell cytoplasm.
So, this is called the
extracellular region or domain,
this is the trans-membrane
region or domain,
and this is the cytoplasmic
region.
Because these molecules can
span across the membrane from
outside to inside,
they're in just the right
position to take messages that
they receive from outside the
cell and transmit them through
the membrane into the cells
internal apparatus,
and that's what they do.
The signal comes in the form of
molecules which we're going to
call throughout the lecture here
'ligands'.
This terminology 'ligand' and
'receptor' you've probably heard
before.
It refers to usually
'receptors' that are fixed in a
cell, on a cell membrane,
and 'ligands' which are
dispersed throughout the body
and free to diffuse around,
and occasionally will find the
cell.
When they do find the cell
they're capable of interacting
with the receptor forming some
kind of chemical interaction
with the receptor.
Now, usually this is a
non-covalent interaction.
There's not actually chemical
covalent bonds that are formed
but it's a non-covalent
interaction, usually dominated
by hydrogen bonding.
We're going to talk about this
kind of non-covalent interaction
more when we talk about the
immune system,
because one example of ligand
and receptors that's important
in the immune system are
antigens - foreign molecules,
and antibodies - molecules that
we produce.
Today let's think about it
more generally as ligands and
receptors.
The ligands are bringing some
message, they transmit the
message by binding to the
receptor.
When they bind,
they produce some change in the
receptor molecule which is
experienced inside the cell.
The way that the cell
experience it is through some
sort of biochemical changes.
Those changes usually involve
enzymes.
They often involve the
generation of what are called
'second messenger' molecules
which carry the signal further
into the cell.
They often involve networks of
reactions, not just one enzyme
but a series of enzymes that
serve to amplify each other.
A reaction performed by one
enzyme creates a product that
stimulates another enzyme that
creates a product,
and stimulates another enzyme,
and through this cascade of
reactions you amplify and carry
the signal forward.
That's what's illustrated
here with the end result being
that there's some change in the
life of the cell.
What would that change be?
Well, it might be that this
signal is a signal to divide.
'It's time for you to
reproduce', and so the cellular
response would be mitosis.
It could be that that signal is
'you need more glucose',
and so the cellular response is
to create more glucose
transporters to bring more
glucose into the cell.
It could be the response is
'there's something dangerous in
the environment,
we got to move away',
and so the response is for the
cell to crawl in the opposite
direction.
There's a diverse range of
responses that might occur,
but that response is initiated
by this simple chemical process
of a ligand binding to a
receptor.
Now, the other thing to
keep in mind is that for any
cell there's not just one
receptor on the cell,
there are thousands,
or hundreds of thousands of
receptors.
All of them could potentially
be receiving signals from a
ligand or a chemical.
So, this pathway might not be
the only one that's being
activated inside the cell at any
given time.
It might be getting a signal
from this receptor and a signal
from this receptor,
and a signal from this
receptor.
What the cell needs to be able
to do is to integrate that
information into a response.
You need to be able to
integrate that information into
a response, and that happens
through these biochemical
reactions.
I hope that makes sense as
background, and I'm just going
to basically illustrate that
basic concept with a few
examples throughout the rest of
the lecture.
The other thing that's on this
slide here is sort of a simple
analogy that I've already
described.
If you think about receptor
ligand system as an input into
the cell.
If it was sound that was being
received that might be beating
of a drum, for example,
that sound gets transduced.
We're used to thinking about
sound being tranduced;
for example,
being converted by acoustic
waves into electrical signals
that can be recognized by your
iPods.
This same thing happens here,
there's a transduction,
one kind of a signal gets
converted to another kind of a
signal.
In the case of a
ligand-receptor,
a chemical signal in the form
of a concentration of ligand
gets converted into a
biochemical signal.
That signal is carried here,
for example,
by the concentration of second
messengers - the concentration
of something else.
Often that signal gets
amplified so it can be used,
same thing happens inside cells
and there's some output that's
generated.
What are - one of the -
this understanding of
receptor-ligand interactions has
been really the biological basis
of much of the pharmaceutical
industry.
Much of the work that
pharmaceutical companies do in
terms of searching for drugs is
searching for new ligands that
activate receptors and create
biological responses inside
cells.
There are two classes,
two broad classes of drug sort
of type ligands that are
defined, agonists and
antagonists.
An agonist is a substance that
mimics the action of a natural
ligand, and I show you a couple
of examples of agonists here.
Now, sometimes the agonist is
the natural ligand itself and
that's - an example of that is
when you use insulin as a drug.
Insulin is a naturally
occurring hormone,
it's a protein hormone that
circulates in all of our bodies
and regulates glucose
metabolism.
When you don't produce enough
insulin yourself,
as diabetics do not,
then you can use insulin as a
drug.
What insulin is doing inside
your body is acting as a ligand
for insulin receptors which
stimulate certain kinds of
cellular responses.
I'll talk about that more in a
minute.
Another example is in the
nervous system,
patients that have Parkinson's
disease have too little of a
natural ligand called dopamine.
That can be supplied by an
antagonist called Aldopa - which
is not exactly the same as
dopamine, it's slightly
different.
It turns out when you give
Aldopa to people,
it gets converted biochemically
into natural dopamine which then
serves as its own agonist.
Sometimes you can design drugs
that act like a natural ligand
without being the natural
ligand.
We've identified many drugs
that stimulate insulin
receptors, for example,
but they're not exactly
insulin,
and those can potentially be
used as agonist type drugs.
An alternate is to design
an antagonist.
This would an example of a
substance that inhibits the
action of a natural ligand and
they can inhibit in a variety of
ways.
Sometimes they inhibit by just
preventing the ligand from
interacting with its receptor.
They prevent the ligand from
reaching its natural receptor,
and so that antagonizes or
inhibits the function of the
natural ligand.
Sometimes they act by actually
binding to the receptor.
They bind sometimes better than
the natural ligand does,
but they don't create the right
biological reaction.
So, they bind to the receptor -
they occupy the receptor so now
the natural ligand can't enter
it but they don't create the
same sequence of biochemical
events.
An example of a drug that works
like that is the anti-cancer
drug Tamoxifen which binds to
estrogen receptors and blocks
estrogen signaling.
Many types of cancers,
particularly breast cancers,
many breast cancers but not
all, are sensitive to estrogen.
Estrogen is a natural signal
for cells to grow.
It's a natural signal for cells
to grow.
and if you design a drug that
blocks estrogen interaction you
stop growth.
Stopping growth in tumors can
be a very beneficial thing.
There's a whole class of
antagonistic drugs that have
been designed to influence your
cardiovascular system.
One class of them is
beta-blockers,
they bind to beta-adrenergic
receptors, which are receptors
that exchange information
between your nervous system and
the contractile system that
beats your heart and that causes
the heartbeat.
They can antagonize that
reaction, and a result they
affect blood rate.
More importantly,
they can affect blood pressure
as well, the strength of your
heartbeat and the pressure that
your heart generates.
These are just some examples.
I mentioned earlier,
we thought about receptors as
being these blocks and membranes
but there are different families
of receptors.
One useful thing about
separating receptors into types
or families is that we found
that many different receptors
work by the same basic
underlying mechanism.
They might have different
ligands which stimulate them,
but once they're stimulated
they work the same way.
Understanding this has really
led to lots of advances in
biology.
We'll talk about that as we
come to it.
What I want to do in here
is just introduce some of the
basic kinds of receptors.
The one that's on the top here
is called ligand-gated ion
channel and an ion channel is a
protein that sits in the surface
of a cell.
It can exist in - a gated ion
channel - can exist in one or
two states.
A state where it's closed,
so imagine a channel with a lid
on top of it;
when it's closed nothing can go
through the channel,
when it's open then things can
go through.
Now, these are special channels
in that they only allow certain
molecules to pass through.
The ones that are most
important in physiology are ones
that only allow ions to go
through: sodium,
potassium, chloride,
calcium, bicarbonate.
We'll see just briefly in this
course if you go onto study
physiology you learn much more,
about how these channels cause
changes in the electrical
potential of cells which lead to
events like conduction of a
nerve,
or contraction of a muscle,
or beating of the heart.
We'll talk a little bit about
that but not much.
For these purposes think
about a channel,
it only allows sodium to go
through for example.
It has a gate on it and that
gate is in open or close state
depending on whether a ligand is
present or not.
If a ligand comes and interacts
with a receptor,
it opens up;
if the ligand goes away,
it closes.
In the presence of this ligand,
this molecule,
it's open, it allows transport
of this ion, when the ligand is
gone it doesn't.
That changes a cell and here's
some examples of it.
Many neurotransmitters that
carry signals between neurons in
your brain work this way.
The cells that take an
electrical signal,
which is coming down your nerve
and convert it into a muscle
contraction work this way,
so 'neuro' nerve,
muscle junctions act based on
ligand-gated ion channels.
Another family is called
the G-protein coupled receptor.
It's called the G-protein
coupled receptor because it's a
receptor, like the one shown
here, that's coupled to a
special molecule called a
G-protein.
When the ligand is present it
binds to the receptor outside
the cell and it activates this
G-protein.
The G-protein then goes on to
create some other biochemical
changes inside the cell.
We're not going to talk about
this in any detail,
there's a little bit more
detail described in your book.
These are fascinating molecules
that turn out to be ubiquitous.
They're everywhere in cells
throughout your body and they
are responsible for lots of the
biochemistry of cell/cell
interaction and signaling.
Another family is receptor
tyrosine kinases,
I'll show another picture in a
moment that tells you more about
what a kinase is,
but a kinase is basically an
enzyme that can add a
phosphorous to another molecule.
It can 'phosphorylate' or add a
phosphorous to another protein.
This is a signal - this passing
of phosphorous - is a signal
that's used very frequently in
intracellular communication.
I'll talk a little bit more
about that in a minute.
In this case,
a receptor tyrosine kinase is a
receptor molecule that binds a
ligand at its surface outside
the cell and initiates this
enzyme activity - this kinase
activity - and causes
phosphorylation of another
molecule.
This is - there are also other
receptors that are linked to
other enzymes besides kinases.
I've included that as a general
family here.
So, these are receptors,
for example,
that bind the ligand and then
liberate an enzyme which
promotes some sort of reaction
inside the cell,
often it's kinases but doesn't
have to be.
One of the enzymes that
often gets activated is an
enzyme which converts ATP,
a small molecule that is inside
all of our cells.
ATP is famous for its ability
to store energy but it's also a
messenger molecule.
When a certain enzyme is
activated inside cells,
ATP gets converted into a
molecule called cyclic AMP,
and cyclic AMP is an example of
one of these molecules called
second messengers.
It gets produced in response to
a signal so there's a binding of
a ligand to a receptor,
the enzyme that does this
conversion is activated and more
cycle AMP is released.
As cyclic AMP levels rise
inside the cell,
something about cell behavior
changes.
Now, one of the advantages
of having second messengers is
this is one way that you can
integrate between different
receptor systems that are acting
inside a cell.
If you have two different
ligands stimulating two
different receptors,
and one causes activation of
this enzyme and generation of
cyclic AMP,
cyclic AMP levels will start to
rise.
If another receptor operating
from a different ligand does the
same thing, generates an enzyme
which causes cyclic AMP to
increase,
the rate of cyclic AMP increase
is going to go up faster than if
only one of these was activated.
The cell is going to experience
something different inside
because both receptors were
activated instead of just one.
Sometimes second messengers
collect signals from a variety
of different receptor systems,
translate them into one kind of
internal change,
and the cell then just has to
know about that one thing
changing.
Does that make sense?
This is another example of a
second messenger,
the inositol lipid pathway.
These are molecules that exist
naturally in cell membranes and
are activated by certain enzymes
and kinases generated by
receptors.
More is said about this in the
book I just include it here as
an example, but it's sort of
beyond the scope of what I
wanted to talk about today.
I did want to say a little
bit more about kinases because
they're so important in
intracellular communication and
kinases take advantage of the
fact that proteins can often
exist in more than one state,
and that's what makes them
useful molecules inside cells.
That's what makes proteins
useful in transmitting or
responding to signals.
Often the state of a protein
depends on whether it's
phosphorylated or not.
Now, being phosphorylated means
that a phosphate group has been
added to the protein,
and phosphate groups can only
be added to certain amino acids
along a protein.
Proteins are only susceptible
to phosphorylation if they have
certain kinds of amino acid
sequences.
One of the amino acids that can
be phosphorylated is tyrosine,
for example.
So, a protein that has tyrosine
and it has tyrosine in a
position such that it's on the
outside of the protein and
accessible to chemical reaction
can be phosphorylated.
What a kinase enzyme does is
that it recognizes this protein,
and for example,
the tyrosine that's on the
protein.
It performs a chemical reaction
on the protein,
taking a phosphorous from ATP
and moving that phosphorous onto
the protein.
Now, you know already,
or you could review in Chapter
4 that I provided to you,
something about how proteins
work.
You know that the function of a
protein is intimately related to
its structure.
Proteins have three dimensional
structures in solution and their
structure determines what they
do.
Sometimes subtle changes in the
structure of a protein can
convert it from an active state
into an inactive state.
That's one of the beauties of
proteins as working molecules is
that their structure can be
changed by subtle means.
Sometimes that subtle change
can lead to a big change in the
function of the protein.
Well, imagine if that change in
structure could be switched on
and off by addition of a
phosphorous;
and in fact it can in many
proteins.
Some proteins can be switched
from an 'off' position where
they don't do anything to an
'on' position where they now do
something by only a chemical
reaction like this where a
phosphorous is added.
Kinases can,
in many cases,
serve as a mechanism for
switching a protein on or
switching a protein off.
If that protein is an enzyme
then you've - and you've
switched it from an 'off'
position where it's not
catalyzing a reaction to an 'on'
position where it is,
you've changed the biochemical
state of the cell,
you've changed the chemical
reactions that can occur within
the cell,
and you've changed its behavior.
That's a very simplified
version of why kinases are
important.
Well, if this kinase
happens to turn this protein on
then you would like to have a
mechanism to turn it off as
well.
The other beauty about -
beautiful thing about proteins
is that if you make subtle
conformational changes,
often those changes are
reversible.
Now, you all know that we can
make irreversible changes in
proteins, you can denature them
completely,
that's what happens when you
cook an egg for example.
You've taken all the proteins
inside the white of the egg,
for example,
you raise the temperature.
Tou make not small changes in
their chemistry but big changes
in their chemistry.
Tou denature them,
you can watch them denature
because the egg white turns from
clear to white and it doesn't go
back.
You've irreversibly changed
that substance because you've
changed the structure of all the
proteins inside.
That - irreversible changes
happen all the time too but here
I'm talking about very subtle
small changes where you're
changing the structure of the
protein but only a little bit
such that it can go back.
One way that you could switch
this on and off inside the cell
is by taking off this
phosphorous,
proteins enzymes that do this
opposite reaction,
the opposite to kinases are
called phosphokinases.
You could imagine a protein
that's existing inside a cell at
some level of abundance.
There are 100 of these
molecules, when a receptor gets
activated a kinase activity gets
activated,
the kinase acts on the protein,
the protein gets switched on,
something new starts to happen
inside the cell.
Another receptor eventually
activates a phosphatase,
that phosphatase now turns the
protein off.
It's a switch that from outside
can be used to change the life
of a cell.
That was some,
not too complicated,
but hopefully understandable
description of a whole area of
biology called signal
transduction.
If you hear about signal
transduction in biology,
people that study signal
transduction are studying just
these things we talked about,
how biochemical messages get
transferred into cells and
through cells.
I want to look at a slightly
higher level of magnification
now and think about different
kinds of cellular communication.
One kind of cellular
communication occurs by similar
mechanisms to what we were
talking about.
Here, there are receptors on
one cell and the ligand that
they experience is not a
dissolved molecule,
but actually a molecule that's
attached to another cell.
Sometimes signals are
transmitted between cells by
cell/cell contact.
By cell/cell contact,
I mean that there's a receptor
in one cell that makes some kind
of a chemical interaction with a
receptor in another cell.
Depending on which cell you are
you would call one the
'receptor' and the other the
'ligand'.
This is a mode of communication
that's used very frequently in
the immune system as we'll see
later.
It's the way,
for example,
that foreign molecules or
antigens get presented to cells
of your immune system in order
to start the process of making
an immune response,
so sometimes a cell/cell
interaction.
The rest of these examples
refer to receptors as I've been
describing them and ligands that
are soluble and can move around
the body.
It's useful to separate these
kinds of signals into three
categories.
One is shown at the top here,
its call autocrine.
This is, maybe,
the strangest because the
ligand that stimulates the
receptor is produced by the cell
itself;
so sometimes cells make signals
that they receive.
This is commonly used in the
immune system as well,
but it's a way of amplifying a
signal.
For example,
what if I activated this cell
by encouraging it to produce
this particular ligand?
That ligand was one for which
the cell had a receptor that
further encouraged it to produce
more of the ligand.
Well, then you could imagine a
cycle here where activation of
the receptor is leading to
production of more ligand,
is leading to activation of the
receptor and production of a
ligand.
That's an example of a process
called positive feedback.
The more the receptor gets
activated the more feedback it
gets to activate.
That can be a very strong
amplifying response,
and that happens in the immune
system in many cases.
An example is production of
certain molecules called
cytokines by T-cells that
activate themselves.
Another example is called
paracrine.
Here, what's different between
autocrine and paracrine is that
there's some distance between
the cell that produces the
signal and the cell that
receives the signal,
but it's not too great a
distance because the blood
system doesn't have to be
involved.
Molecules are produced here and
they flow directly over,
usually by diffusion,
to the neighboring molecule.
'Para' means near,
'paracrine' means 'a signal
from nearby'.
Endocrine are signals that
get carried through the blood
system.
The cell that's producing the
signal produces enough of the
molecule so that it enters the
bloodstream,
it circulates throughout your
body, eventually it reaches a
cell at a great distance,
which has a receptor for that
ligand and the signal gets
received.
An example of that is,
of course, insulin which is
produced by cells of the
pancreas and acts on cells all
over the body.
Adrenaline is another one,
produced by cells in your
adrenal gland but used by cells
all over your body.
Well, the endocrine system
is a body organ system that is
specialized in producing these
kinds of signals that are used -
that accumulate in the blood and
are used by cells all over the
body.
There are two general classes
of molecules that are produced
by the endocrine system.
All of the molecules are called
hormones, so a hormone is
another name for a ligand that
operates in this endocrine
fashion.
A hormone is just a ligand that
operates in this endocrine
fashion.
Hormones can be proteins,
endocrine hormones can be
proteins, meaning they're large
molecules that are usually
fairly water soluble,
or they can be steroids.
Steroids are small molecules -
much smaller than proteins -
smaller molecules that tend to
be hydrophobic or lipid soluble.
Example, protein hormones are
insulin which we've talked about
before and glucagon,
and growth hormone which we
haven't talked about but that's
very important during periods of
life like adolescence,
for example,
when rapid growth of your bones
is occurring.
Well, insulin is a protein,
it's produced by cells in the
pancreas, it circulates in your
blood.
It can't enter cells because
it's too big and it's too water
soluble so it can't go through
cell membranes.
So, it interacts with receptors
called insulin receptors that
are on cells that are sensitive
to insulin.
Steroid hormones,
on the other hand,
molecules like testosterone and
estrogen,
progesterone,
the sex steroids that determine
sexual characteristics and are
important for reproductive
function are molecules that are
all derived from a similar
source.
Many of them are derived from
cholesterol and they're
hydrophobic, which means they
can penetrate through cell
membranes.
So, it doesn't need to bind to
a receptor on the surface of the
cell in order to work because
the molecule can actually enter
the cell directly.
Many steroid hormones act
because they bind to cellulars -
to receptors that are deep
within the cell,
often inside the nucleus.
I'll show how that works in
just a moment,
but estrogen for example,
is one of those.
When estrogen is present it can
enter cells in the vicinity and
it can bind to receptors that
are deep inside cells.
This is a new concept,
receptors don't have to be
these molecules on cell surface,
there can be receptors that
exist in other places within the
cell, for example.
Go a little bit further
with this schematic and talking
about what insulin does.
You know about this but maybe
you haven't thought about it at
this level of detail,
but you know that when you -
after you eat,
you eat lunch for example.
After class you're going to go
to lunch, you're going to eat
whatever you eat.
Hopefully it's not a Snickers
bar but let's assume it is a
Snicker's bar and your blood
glucose is going to rise because
you're taking a lot of sugar in.
When it does your pancreas
receives a signal that your
blood glucose has started to go
up, and it will secrete insulin.
So, there are cells in your
pancreas which recognize glucose
levels and they secrete insulin
in response.
When they do that,
this insulin then starts to
circulate throughout the blood.
If you measured,
if somebody measured levels of
insulin in your blood after
lunch,
if they took it ten minutes,
30 minutes, an hour,
you would see that it's going
slowly up.
As it's going up,
it's circulating around your
body.
Most cells in your body have
insulin receptors so insulin is
starting to bind to insulin
receptors on those cells.
When it does it makes
biochemical changes inside the
cells and one of the things it
does is increase glucose uptake
into certain kinds of cells,
particularly fat cells and
muscle cells.
Well, why does it increase
uptake of glucose into muscle
cells?
Because muscle can use and
frequently is using glucose as a
source of energy.
So, when there is extra glucose
you want to put it into the
cells that can use it
immediately.
Why does it go into fat
cells?
Because maybe you ate more
glucose than you needed
immediately and so it goes into
cells that can store glucose.
That's what fat cells do,
they convert glucose into a
form for storage.
Well, how does glucose uptake
get enhanced in those cells?
It gets enhanced because when
insulin binds to the insulin
receptor, it activates the
receptor.
How does it activate it?
It generates a kinase activity
which leads to phosphorylation
of the protein.
Insulin binding leads to
phosphorylation,
leads to other biochemical
changes.
Eventually what happens is that
glucose transport molecules
which are expressed and stored
inside the cell get shuttled up
to the surface,
so the cells permeability to
glucose goes up and more glucose
can come in.
This is a highly simplified
version, but sort of closes the
loop on what we've been talking
about.
Insulin, the ligand binds to
its receptor,
creates a change through a
kinase activity that's exposed,
which leads to other
biochemical changes,
which leads to a change in cell
behavior - in this case the cell
behavior is that more glucose
transporters are brought to the
membrane and more glucose can
enter the cell.
Does this make sense?
Sometime after you've
eaten, say you had this Snickers
bar at lunchtime and you don't
have time to get anything else
to eat during the day,
your blood glucose level will
go down.
Why does it go down?
Well, one because you're not
taking anymore glucose in,
but the other because when you
did eat glucose you got more
insulin and the glucose got
shuttled into cells where it's
either used or stored.
So, that brings your glucose
level down.
Another hormone gets produced
by the pancreas in response to
low glucose levels,
it's called glucagon.
It has many of the opposite
effects that insulin has,
so not only does insulin go
down and stop these behaviors
but a new hormone called
glucagon gets produced which
reinforces that change.
These - you're going between
these states throughout the day.
Where your cells experience
those states is through these
extra cellular ligands called
insulin and glucagon.
Steroid hormones can
operate in a different way
because of their structure.
They're small molecules,
they're lipid soluble,
they can go from extracellular
to intracellular.
Let's take an example of
estrogen, for example.
A small molecule gets produced
by cells in one part of the
body, circulates in the blood,
estrogen enters cells,
and sometimes that estrogen is
able to penetrate deep within
the cell,
even into the nucleus.
The receptor for estrogen is a
special molecule called a DNA
binding factor.
Estrogen can combine with this
receptor to form a new sort of
unit which interacts with DNA.
When this bound receptor
interacts with DNA it could,
for example,
turn on expression of a target
gene.
One of the things that estrogen
does when cells are exposed to
estrogen is that certain genes
get turned on that weren't
turned on in the estrogen-free
state.
It leads to expression of new
genes, production of new
proteins, and a change in a
behavior of the cell.
Sometimes receptors,
when they interact with
ligands, create changes in what
proteins are actually being
produced by the cell.
This is one very direct way for
that to happen.
These kinds of molecules which
activate genes,
they're activating the process
of transcription.
They're sometimes called
transcription factors and this
is an example of a transcription
factor that is itself activated
or turned on by the presence of
a steroid.
That's the end of what I wanted
to say today.
What we're going to talk about
next time, and I encourage to
read ahead because you'll see
that there's a lot more detail
in Chapter 6 than what we're
talking about here,
I've emphasized the main
points, the ones that I think
are important,
that are clearly important for
your understanding.
We're going to take these
general topics and talk about
how they work in the nervous
system and the immune system
next time.
