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So systems refer to,
as in any case, something working

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together.  In the case of biology,
systems working together for a

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specific function.
The tissues and the cells working

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together to a specific function.
We're going to begin with a

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discussion of the nervous system.
Let me write this on the board

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because you really need to
know this definition.

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Many organs or tissues collectively

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giving one function.
And we're going to begin with a

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discussion of the nervous system.
The function of the nervous system

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is one of communication.

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But that single term communication
really belies the complexity and the

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enormity of the nervous system.
Could I please have a couple of

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letter carriers?
Why don't you [do the other side?

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.  So you can do each side.  OK?
All right.  OK.

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So we're going to talk about the
nervous system and its role in

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communicating.
Communicating things coming from

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the outside in,
communicating things that happen

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within your body.
Within the nervous system there is

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one type of cell that is the most
important cell with regard

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to communication.
And the term, the name of that cell

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type is a, wait.
I've got a new system here.

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A neuron.  Very good.  Excellent.
Right.  It's sort of your moment of

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fame.  But you have to be careful,
I might hand the microphone over for

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the rest of the lesson.
OK.  So the cell type that you need

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to know is the neuron.
And the neuron is really a curious

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cell.
In my opinion,

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it's one of the cells that is really
one of the ancestral cell types.

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In fact, I think it might have been
one of the first cell types because

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the thing that all cells really have
in common, whether they live as

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single-celled organisms or as
multicellular organisms,

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is a way of sensing what's around
them.  Even single-celled animals

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sense whether or not there are
particular chemicals around them.

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I showed you in the morphogenesis
section the dictyostelium,

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single-cells moving towards a cyclic
AMP source.  Those are single-cells

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sensing their environment.
And I think ancestrally this kind

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of sensing of one's environment by a
cell might have been the first

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function that really was encoded
about the basic functions that

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allowed a cell to replicate
in the first place.

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So if you look at all multicellular
animals, this is taken from your

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book, all multicellular animals,
you can find networks of neurons

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that serve as the wires for this
communication network within an

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animal.  The nervous system begins
to develop very early during human

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development.  By 19 days after
fertilization you can pick out a

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region that is going to become
the future brain.

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In studies in my own laboratory
we've shown, using frogs and fish as

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models, that you can find cells that
know, that are determined as nervous

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system cells when the embryo is
still a ball of cells.

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So in human equivalent terms,
when it's really less than two

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week's old, you can find cells that
are expressing genes that are

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characteristic of the nervous system.
So the nervous system starts to

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develop very early.
Now, the cell type characteristic

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of the communication part of the
nervous system is the neuron.

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And it has two interesting features.
Its interesting features are called

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dendrites and axons.
The dendrites and axons are both

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processes that project out from a
cell body.  Now,

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the cell body is where the nucleus
lies, and these dendrites and axons

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are processes,
some of which are extremely long.

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So this is a single cell.
And some axons can be a meter in

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length.  So there are axons that
arise at the base of your spine,

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where they exit your spine, and they
extend all the way down most of your

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legs.  So they can be a meter or
more long.  That is a single-celled

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process.  So that's very thin,
OK?  Not as thin as DNA but it's

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very thin.  And it must
be fairly robust.

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Usually axons are bundled together
and tied together by other tissue to

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make them more robust.
But they are very long.

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And neurons communicate by means of
these very long processes connected

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one to another.
And we'll talk more about that in a

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moment.

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Now, the way the nervous system is
organized is actually rather

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peculiar and it isn't intuitively
obvious that it would be

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organized in this way.
Neurons, let me set this up,

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communicate, do a lot of their
communication intracellularly,

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that is within one cell.

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And, actually,
let me hold off on that until the

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next board.  Within one cell,
as opposed to having multiple little

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cells all next to one another that
have conversations with one another.

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OK?  So you'll have a neuron that
extends an axon that could be as

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long as these tables.
And that neuron will then

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communicate with another one next
door in a kind of wiring diagram.

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You could imagine an alternate way
of communication where you had a

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little cell sitting next door to
another cell, another cell,

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another cell, another cell and so on.
And you would get the same pathway,

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you'd get the same circuitry, but it
would be an intercellular means of

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communication.
And it's interesting to consider

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why that hasn't happened.
It probably hasn't happened because

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it's faster, for reasons I'll
explain in a bit,

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to communicate within the cell than
between cells.

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So the neuron exploits for its
communication its intracellular

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communication.

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Something that's present in all
cells.  And this is a potential

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difference across the plasma
membrane.  So all cells,

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as far as we know, have a potential
difference across the membrane.

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And this is a number you probably

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ought to know.
It's about 60 millivolts.

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Now, that doesn't sound that much,
but if you extrapolate that into

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terms that we think about and think
about the width of the plasma

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membrane which is just a few
nanometers, that's actually a very

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large voltage difference.
And if you do the calculations,

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you actually come to the conclusion
that the potential difference across

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a cell membrane is about 100 fold
higher than it is in high voltage

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power lines, OK,
but it's very little.

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The actual numbers are very little,
and so you don't realize that.  But

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it's a very substantial potential
difference.  And what I'm going to

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tell you is that the neuron exploits
this potential difference for

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intracellular communication.
Now, all cells have got this

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potential difference.
And in most cells, and there must

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be some reason all cells do,
otherwise it wouldn't be maintained.

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But I must say for most cells it's
not really understood why you have

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this potential difference across the
membrane.  OK.

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Moving on.  There are lots of
different shaped neurons.

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You can look at your book for a
diagram.  These are some actual

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pictures that are taken of silver
stained neurons.

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Neurons take up silver dyes very
effectively and show up as black.

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And you can see here is one with
lots of processes.

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Here are some with much fewer
processes.  Here's one that is much,

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here are some that are much more
tangled and so on.

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So there are many different shapes
and forms of neurons.

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There are about 200 different
recognizable neuronal cell types,

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and they're found in different parts
of the nervous system and

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do different things.
And as we move through these

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lectures, what I'm going to do is
talk about today intracellular

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communication,
next time I'll talk about

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communication between cells,
and in the third lecture of the

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nervous system module I'll talk
about how the wiring circuitry is

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set up in the organism.
But today the focus is going to be

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communication within the
neuron.  All right.

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So I'm going to summarize that a

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little more because I want you to be
with me.  So some kind of input.

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The notion is that some kind of
input impinges on the dendrites,

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the dendritic processes of a neuron.
And these dendrites communicate

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this information often through the
cell body, not always,

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to the axon of the same cell.
And this axon then communicates to a

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dendrite of another adjacent cell.

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And that dendrite communicates with
the axon and so on.

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So one can distinguish two different
kinds of communication here.

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The first is the one that I have
told you already,

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intracellular communication.
And this is an electrical ionic

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movement.  Well,
this is an electrical communication.

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And it involves the movement of
ions.  And the second kind of

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communication is between
one cell and another.

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This is intercellular across
something called a synapse,

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or synapse, depending on your
preference.  And this is usually a

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chemical kind of communication,
although in some instances it can be

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electrical.  OK?
And so, again, today's lecture

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we're going to talk about
intracellular communication and on

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Wednesday we'll talk about this
intercellular communication or

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synaptic communication.

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All right.  So let me go through
briefly on the board the notion of

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how a neuron sends a signal from its
point of origin along the length of

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this very long axon,
or usually fairly long axon or

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sometimes long axons.
Axons can be very different lengths,

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but they generally are much longer
than your regular somatic cell which

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is just about 10 microns in diameter.
How is this intracellular

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communication affected?
So what I'm going to do is to draw

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you part of a cell.
We'll get to your diagrams in a

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moment, but I'm going to draw you
part of a cell.

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So this is the axon,
part of an axon.

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PM is the plasma membrane.
And let me take just one piece of

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that plasma membrane and magnify it
over here.  So we can have out and

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we can have in.
And the deal is this.

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The cell is set up, and we'll talk
about how in a moment,

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such that it is more positively
charged in the extracellular

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environment than it is in the
intracellular environment.

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And that is stable.
And it's stable at a particular

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potential that I've given you
already, the 60 millivolts,

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which is called the resting
potential.  Now,

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along comes some kind of input,
a sound, a touch, some food that

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you've eaten.
And the neuron is told that there's

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an input.  And what this does is in
one portion of this axonal cell

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membrane, plasma membrane,
it reverses the polarity transiently

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and very profoundly such that --

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-- in this region,
I'll just circle it.

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I think it's easier.
In this region of the plasma

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membrane you have switched the
polarity.  This switching of

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polarity gives a change in potential
difference.  It almost reverses the

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potential difference completely.
So whereas it's minus 60 millivolts

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in your resting potential inside to
outside, it almost completely

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reverses to about plus
50 millivolts.

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And this reversal of polarity --

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-- is given the name a
depolarization or is a

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depolarization.
And its neurobiology term,

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which you must know, is an action
potential.

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All right.  So this is very
interesting, but what's even more

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interesting is what happens next.
And so you should be asking at this

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point, well, how does that happen?
And I'll tell you that in a bit.

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But what even more interesting is
what happens next because that

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depolarization,
that action potential then moves

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along the neuron.
So if we draw a couple more,

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we actually only need to draw one
more view of our cell membrane,

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after some period of time, and this
is a millisecond timeframe here.

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After the millisecond timeframe,
that initial depolarization reverses,

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and next door the membrane
depolarizes.

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OK.  So the signal then propagates

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along the neuron,
along the axon in a particular

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direction.  And you're going to ask
now, well, how does it know which

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direction to propagate in?
And I'll tell you that in a moment,

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too.  Interestingly, the action
potential is all or none.

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You either reverse the polarity
completely or you don't.

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You don't get a little action
potential or a big action potential.

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You get an action potential.  OK?
And that's important to know.

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00:17:43,000 --> 00:17:49,000
So that is enough to start.  And if
you look at the handout I gave you

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today, if you don't have look at the
one next door or come and zip down

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00:17:54,000 --> 00:18:00,000
here and get one, that
would be fine.

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I have in my first cartoon the
outside of the cell and the inside

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00:18:04,000 --> 00:18:08,000
of the cell.  Now,
I've shown these as completely

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00:18:08,000 --> 00:18:12,000
positive and completely negative.
That is a lie.  They are not.  OK?

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There is a potential difference.
And so there's a charge distribution

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that's unequal,
but it is certainly not completely

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positive and completely negative.
That is for cartoon purposes only.

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So here's your resting potential
and here's input from the

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outside of the cell.
And what happens,

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to initiate this action potential,
is that there is a small change in

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00:18:38,000 --> 00:18:43,000
the membrane potential.
It just changes a little bit such

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that it's now at minus 50 millivolts
or so instead of minus 60 millivolts.

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00:18:49,000 --> 00:18:54,000
And that is enough of a trigger to
tell that membrane,

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and the membrane right next door,
to depolarize and to give a

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full-blown action potential.
So now that piece of the membrane

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00:19:04,000 --> 00:19:08,000
has reversed its polarity.
Positive charges have rushed into

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the cell.  I'll talk about this more
in the mechanism in the moment.

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Positive charges have rushed into
the cell, or positive ions have

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00:19:18,000 --> 00:19:22,000
rushed into the cell,
and you've got your action potential.

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So the action potential is this
reversal in membrane polarization,

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this depolarization.
The action potential gives you an

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00:19:32,000 --> 00:19:36,000
unequal charge distribution within
the cell, so you've got these

225
00:19:36,000 --> 00:19:40,000
positive ions around.
And they actually start defusing a

226
00:19:40,000 --> 00:19:45,000
little bit.  Now,
the axon is not a very good current

227
00:19:45,000 --> 00:19:49,000
conductor.  Charges leak out of it.
And very rather quickly and in an

228
00:19:49,000 --> 00:19:53,000
active way this charge in equality
will be redistributed.

229
00:19:53,000 --> 00:19:58,000
But it does leak a little bit.
It moves a little bit by diffusion.

230
00:19:58,000 --> 00:20:02,000
And, as it does so,
it depolarizes the membrane next

231
00:20:02,000 --> 00:20:07,000
door just a tad to this threshold
potential.  And that will make this

232
00:20:07,000 --> 00:20:11,000
membrane next door amenable to an
action potential and it will

233
00:20:11,000 --> 00:20:16,000
depolarize, and so will get an
action potential next door.

234
00:20:16,000 --> 00:20:20,000
Now, I drew up here on the board
that you get, in the first place

235
00:20:20,000 --> 00:20:25,000
where there was an action potential,
the redistribution of charges again

236
00:20:25,000 --> 00:20:30,000
so that you get rid of the positive
charges on the inside.

237
00:20:30,000 --> 00:20:33,000
And I've depicted this here.
OK?  So here are the charges from,

238
00:20:33,000 --> 00:20:37,000
this is all on your handout, guys,
OK?  These are the first,

239
00:20:37,000 --> 00:20:41,000
I believe, three figures on your
handouts.  So look at them and make

240
00:20:41,000 --> 00:20:45,000
notes, but you certainly don't need
to draw these.

241
00:20:45,000 --> 00:20:48,000
OK.  So here I've depicted the axis
positive charges,

242
00:20:48,000 --> 00:20:52,000
the axis positive ions being moved
back out of the neuron.

243
00:20:52,000 --> 00:20:56,000
And I've put these circles with a
line through the middle which

244
00:20:56,000 --> 00:21:00,000
conventionally means no
something or other.

245
00:21:00,000 --> 00:21:04,000
And what it means in this case is
that this membrane that had just

246
00:21:04,000 --> 00:21:09,000
been part of an action potential is
now no longer competent to elicit

247
00:21:09,000 --> 00:21:13,000
another action potential.
There's some kind of inhibition

248
00:21:13,000 --> 00:21:18,000
that's been put on it so it cannot
give another action potential.

249
00:21:18,000 --> 00:21:23,000
So it re-polarizes, but it cannot
re-depolarize.

250
00:21:23,000 --> 00:21:27,000
And, again, there is about a
millisecond timeframe window before

251
00:21:27,000 --> 00:21:32,000
it can depolarize again.
And you can do the same thing.

252
00:21:32,000 --> 00:21:36,000
You can get the action potential
moving up along the neuron.

253
00:21:36,000 --> 00:21:40,000
Here's the direction of propagation.
And the direction of propagation is

254
00:21:40,000 --> 00:21:45,000
a result of diffusion,
slight diffusion of the positive

255
00:21:45,000 --> 00:21:49,000
ions that are coming in during the
depolarization that change the

256
00:21:49,000 --> 00:21:53,000
threshold, that change the membrane
potential right next door to a

257
00:21:53,000 --> 00:21:58,000
threshold potential which allows the
action potential to be triggered.

258
00:21:58,000 --> 00:22:05,000
And the propagation direction is
unidirectional because the membrane

259
00:22:05,000 --> 00:22:12,000
that has just depolarized,
that previously depolarized is no

260
00:22:12,000 --> 00:22:19,000
longer able to re-depolarize for
some lag period.

261
00:22:19,000 --> 00:22:27,000
Yes?  Maybe?  Whatever?
All right.  We'll go with whatever

262
00:22:27,000 --> 00:22:33,000
category.
OK.  I always have to work at this.

263
00:22:33,000 --> 00:22:37,000
OK?  I study this stuff and it
takes me a while.

264
00:22:37,000 --> 00:22:41,000
So think about it.
It's actually a very elegant

265
00:22:41,000 --> 00:22:45,000
strategy by the cell.
You'll deal with this more on

266
00:22:45,000 --> 00:22:49,000
problem sets.  All right.
So let me move on.  And let me move

267
00:22:49,000 --> 00:22:53,000
onto the question,
actually, I'm not going to move onto

268
00:22:53,000 --> 00:22:57,000
this question.
Yes.  I'm going to move onto,

269
00:22:57,000 --> 00:23:02,000
all right.
I will move onto this question.

270
00:23:02,000 --> 00:23:06,000
I'm going to tell you more next
time that the action potential

271
00:23:06,000 --> 00:23:10,000
initiates at one particular place in
the cell which is right at the place

272
00:23:10,000 --> 00:23:14,000
where the axon starts.
And that is called the axon hillock.

273
00:23:14,000 --> 00:23:18,000
And we'll talk more about this next
time when we talk about synapses.

274
00:23:18,000 --> 00:23:22,000
I do want to very briefly address
the speed of propagation of the

275
00:23:22,000 --> 00:23:26,000
action potential.
So it's been calculated that action

276
00:23:26,000 --> 00:23:30,000
potentials move at a speed such that
you, if you ran the length of a

277
00:23:30,000 --> 00:23:34,000
football in one second,
that is how fast the action

278
00:23:34,000 --> 00:23:39,000
potential is propagating down the
neuron. OK?  So you can do the

279
00:23:39,000 --> 00:23:43,000
calculation of how many meters per
second it is.  It's very,

280
00:23:43,000 --> 00:23:47,000
very rapid.  OK?  So you could get a
nerve impulse in milliseconds going

281
00:23:47,000 --> 00:23:52,000
from one part of your body to
another.  It's actually interesting,

282
00:23:52,000 --> 00:23:56,000
though, it's not that rapid.  And
you've probably all had the

283
00:23:56,000 --> 00:24:01,000
sensation of touching a hot stove or
something hot.

284
00:24:01,000 --> 00:24:05,000
And it takes you a moment before you
actually realize that you've touched

285
00:24:05,000 --> 00:24:09,000
the hot stove.
And then realize and you remove

286
00:24:09,000 --> 00:24:13,000
your finger.  That lag,
that moment of realization is a

287
00:24:13,000 --> 00:24:17,000
measure of your action potentials
getting to your brain and then your

288
00:24:17,000 --> 00:24:21,000
brain saying, wow,
or not even quite in your brain

289
00:24:21,000 --> 00:24:25,000
saying, ooh, I better move my finger.
So that's actually a measure.

290
00:24:25,000 --> 00:24:30,000
There is a finite time that
propagation takes.  OK.

291
00:24:30,000 --> 00:24:35,000
Now, propagation of action
potentials can be increased by

292
00:24:35,000 --> 00:24:40,000
increasing the diameter of a neuron.
The fatter the diameter the greater

293
00:24:40,000 --> 00:24:45,000
the, the lower the surface area to
volume ratio the more that current

294
00:24:45,000 --> 00:24:50,000
can move within the cell before
being dissipated in various ways.

295
00:24:50,000 --> 00:24:55,000
And things like invertebrates, so
the squid for example,

296
00:24:55,000 --> 00:25:00,000
has got axons which are a millimeter
in diameter.

297
00:25:00,000 --> 00:25:04,000
They're called squid giant axons.
They've very popular preparations

298
00:25:04,000 --> 00:25:08,000
to be used in neurobiological
studies because they're so big.

299
00:25:08,000 --> 00:25:12,000
And they are very, they transmit an
action potential very rapidly,

300
00:25:12,000 --> 00:25:16,000
or they propagate it very rapidly
because they've got this high volume

301
00:25:16,000 --> 00:25:20,000
to surface area ratio.
We do not do that to increase the

302
00:25:20,000 --> 00:25:24,000
speed of propagation.
What we do instead is to wrap our

303
00:25:24,000 --> 00:25:28,000
axons in insulation.
And the insulation we wrap our

304
00:25:28,000 --> 00:25:33,000
axons in is called myelin.
It's secreted by cells called

305
00:25:33,000 --> 00:25:37,000
Schwann cells that are part of a
system of support cells in the

306
00:25:37,000 --> 00:25:42,000
nervous system called the glia.
And these myelin sheaths that wrap

307
00:25:42,000 --> 00:25:46,000
around the neuron do two things.
Firstly, they prevent leakage of

308
00:25:46,000 --> 00:25:51,000
current as it moves along inside the
axon.  And so you get rapid

309
00:25:51,000 --> 00:25:55,000
propagation of current inside the
axon.  And, secondly,

310
00:25:55,000 --> 00:26:00,000
you get depolarization only at
specific places where there is a

311
00:26:00,000 --> 00:26:05,000
break in this insulating
myelin sheath.

312
00:26:05,000 --> 00:26:08,000
From your book,
this is front your book.

313
00:26:08,000 --> 00:26:11,000
And from your book also I have
taken this diagram where,

314
00:26:11,000 --> 00:26:14,000
it's actually hard to see here,
but this is a break between the

315
00:26:14,000 --> 00:26:18,000
myelin sheath.
It's called a Node of Ranvier.

316
00:26:18,000 --> 00:26:21,000
And here is where you get
depolarization.

317
00:26:21,000 --> 00:26:24,000
The ions that cause the
depolarization rapidly move along

318
00:26:24,000 --> 00:26:28,000
inside the axon to the next place
where depolarization

319
00:26:28,000 --> 00:26:32,000
can take place.
And that really increases the speed

320
00:26:32,000 --> 00:26:36,000
of propagation of a signal in our
own neurons.  All right.

321
00:26:36,000 --> 00:26:41,000
But, you might be asking,
how is this potential difference set

322
00:26:41,000 --> 00:26:46,000
up and how is propagation occurring
at the mechanistic level?

323
00:26:46,000 --> 00:26:50,000
I've thrown out charge movement,
ion movement in a somewhat

324
00:26:50,000 --> 00:26:55,000
undirected way,
but let's try to be more directed

325
00:26:55,000 --> 00:27:00,000
now and talk about what
is actually happening.

326
00:27:00,000 --> 00:27:04,000
And the thing that's really
important to know about is a set of

327
00:27:04,000 --> 00:27:08,000
proteins, actually,
two sets of proteins.

328
00:27:08,000 --> 00:27:13,000
One are called ion channels and the
other are called pumps.

329
00:27:13,000 --> 00:27:17,000
So the membrane is a wonderful
thing.  They insulate cells from one

330
00:27:17,000 --> 00:27:22,000
another.  It allows the cells to
function as a unit.

331
00:27:22,000 --> 00:27:26,000
And, indeed, it allows
intracellular organelles

332
00:27:26,000 --> 00:27:31,000
to function as a unit.
But there is an issue with the

333
00:27:31,000 --> 00:27:35,000
membrane in that it's insulating.
And very little can get across it

334
00:27:35,000 --> 00:27:39,000
unless it's a hydrophobic something.
So anything hydrophilic, including

335
00:27:39,000 --> 00:27:43,000
water, cannot cross the plasma
membrane.  And so you have to now

336
00:27:43,000 --> 00:27:47,000
devise, you've got this great
invention of the membrane,

337
00:27:47,000 --> 00:27:51,000
but now you've got to devise a way
to actually get things in and out of

338
00:27:51,000 --> 00:27:55,000
the cell.  And this is where
channels and pumps come in.

339
00:27:55,000 --> 00:28:01,000
So an ion channel is a protein,
or usually a set of proteins that

340
00:28:01,000 --> 00:28:08,000
work together,
that make a channel,

341
00:28:08,000 --> 00:28:15,000
a pore or a channel in the plasma
membrane.

342
00:28:15,000 --> 00:28:23,000
There are a couple of different

343
00:28:23,000 --> 00:28:27,000
kinds of channels you should know
about.  All of them are selective.

344
00:28:27,000 --> 00:28:35,000
Selective means that they let some

345
00:28:35,000 --> 00:28:40,000
things through and don't let other
things through.

346
00:28:40,000 --> 00:28:45,000
Some of them are open all the time.
They also may be called leaky.  I

347
00:28:45,000 --> 00:28:50,000
don't really like that term.
I think open is a better term.

348
00:28:50,000 --> 00:28:55,000
And some of them have regulated
opening.  They're closed but they

349
00:28:55,000 --> 00:29:01,000
can be opened.
And these are called gated channels.

350
00:29:01,000 --> 00:29:05,000
Another class of proteins that you
need to know about are the pumps.

351
00:29:05,000 --> 00:29:09,000
Pumps are also proteins that sit in
the plasma membrane.

352
00:29:09,000 --> 00:29:13,000
And they transport things across
the plasma membrane,

353
00:29:13,000 --> 00:29:17,000
too, but unlike channels which are
literally pores through the membrane

354
00:29:17,000 --> 00:29:21,000
and things can move through by
diffusion, pumps use ATP to

355
00:29:21,000 --> 00:29:26,000
transport things across
the cell membrane.

356
00:29:26,000 --> 00:29:33,000
And you can have things going into

357
00:29:33,000 --> 00:29:37,000
the cell, you can have things going
out of the cell,

358
00:29:37,000 --> 00:29:42,000
and you can have things going both
ways at kind of the same time.

359
00:29:42,000 --> 00:29:47,000
And ion channels are really key
here in terms of setting up the

360
00:29:47,000 --> 00:29:51,000
membrane potential and propagating
an action potential.

361
00:29:51,000 --> 00:29:56,000
This is a reconstruction of an
x-ray crystalographic analysis

362
00:29:56,000 --> 00:30:01,000
of an ion channel.
So what you can see is that there

363
00:30:01,000 --> 00:30:05,000
are nine, eight different proteins
that are arrayed together to form

364
00:30:05,000 --> 00:30:10,000
this circle.  And in the middle is a
hole, literally,

365
00:30:10,000 --> 00:30:14,000
and that is the pore.
And that is the pore through which

366
00:30:14,000 --> 00:30:18,000
the ion will move.
And it's very interesting that the

367
00:30:18,000 --> 00:30:23,000
selectivity of an ion channel,
well, how do you get a ion channel

368
00:30:23,000 --> 00:30:27,000
selected?  Well,
it hasn't been clear until this kind

369
00:30:27,000 --> 00:30:31,000
of analysis, which is fascinating.
So here is a potassium channel down

370
00:30:31,000 --> 00:30:35,000
here.  So this is something that
lets potassium through,

371
00:30:35,000 --> 00:30:39,000
but it will not let sodium through,
even though sodium is smaller than

372
00:30:39,000 --> 00:30:43,000
potassium, that sodium ions are
smaller than potassium ions.

373
00:30:43,000 --> 00:30:47,000
So how does that work?  Well,
the way it seems to work is that the

374
00:30:47,000 --> 00:30:51,000
ions get through the pore if the
pore doesn't know they're there or

375
00:30:51,000 --> 00:30:55,000
if the ion doesn't know it's going
through a pore.

376
00:30:55,000 --> 00:30:59,000
So if the ion cannot distinguish
whether it's interacting with water

377
00:30:59,000 --> 00:31:03,000
in solution or with the ion channel,
it will be able to diffuse through

378
00:31:03,000 --> 00:31:07,000
the pore.
If it can distinguish it

379
00:31:07,000 --> 00:31:11,000
thermodynamically it will not.
So here's an example.  Here is

380
00:31:11,000 --> 00:31:15,000
potassium interacting with water.
Notice the spacing of the oxygens

381
00:31:15,000 --> 00:31:20,000
and the potassium.
And here's sodium interacting with

382
00:31:20,000 --> 00:31:24,000
water.  And you can see that since
sodium is smaller the oxygen,

383
00:31:24,000 --> 00:31:29,000
the spacing of the oxygens and the
sodium is closer, tighter.

384
00:31:29,000 --> 00:31:33,000
When potassium goes through the pore
it turns out that there are a number

385
00:31:33,000 --> 00:31:37,000
of oxygen sticking out into the pore,
and they interact with potassium in

386
00:31:37,000 --> 00:31:41,000
exactly the same disposition with
exactly the same spacing as those

387
00:31:41,000 --> 00:31:46,000
water molecules in water.
So this potassium ion cannot tell

388
00:31:46,000 --> 00:31:50,000
whether it's interacting with water
or whether it's traveling through

389
00:31:50,000 --> 00:31:54,000
the pore.  On the other hand,
if the sodium ion were to get near

390
00:31:54,000 --> 00:31:58,000
the pore its charge interactions
would not be the same as

391
00:31:58,000 --> 00:32:02,000
they are in water.
It would only be able to interact

392
00:32:02,000 --> 00:32:06,000
with two of the oxygens and not the
other two.  And this is

393
00:32:06,000 --> 00:32:10,000
thermodynamically unfavorable,
and it would not be able to go

394
00:32:10,000 --> 00:32:14,000
through the pore.
So this is a very recent and very

395
00:32:14,000 --> 00:32:18,000
beautiful explanation of how pores
can be selective.

396
00:32:18,000 --> 00:32:22,000
The ions go through one at a time
in single file,

397
00:32:22,000 --> 00:32:26,000
and they can go through very rapidly
because this is a diffusion driven

398
00:32:26,000 --> 00:32:30,000
process.  OK.  Now,
what about these gated channels?

399
00:32:30,000 --> 00:32:34,000
I've shown here,
from your book, a picture of an open

400
00:32:34,000 --> 00:32:38,000
channel and a gated channel that is
open sometimes and closes at other

401
00:32:38,000 --> 00:32:42,000
times.  The voltage gated sodium
channel, we'll talk more about in a

402
00:32:42,000 --> 00:32:47,000
moment, is a particularly important
channel.  And this is a diagram that

403
00:32:47,000 --> 00:32:51,000
is, you know, it's a diagram but it
will illustrate two points that I

404
00:32:51,000 --> 00:32:55,000
want to make.  Firstly,
you can find a state of a gated

405
00:32:55,000 --> 00:33:00,000
channel where it's closed and it
won't let any ions go through.

406
00:33:00,000 --> 00:33:04,000
Upon a stimulus that channel will
open and it will let the ions

407
00:33:04,000 --> 00:33:08,000
through.  And then what seems to
happen is that there's some kind of

408
00:33:08,000 --> 00:33:12,000
lash back where the channel says
uh-oh, and there's some feedback

409
00:33:12,000 --> 00:33:16,000
that goes and closes the channel.
But it's not in the same way that

410
00:33:16,000 --> 00:33:20,000
it was closed in the first place.
And so I've called that an

411
00:33:20,000 --> 00:33:24,000
inhibition or closing or being
refractory.  And if you think about

412
00:33:24,000 --> 00:33:28,000
what I told you about propagation of
information along a neuron,

413
00:33:28,000 --> 00:33:32,000
you'll be able to see why I am
starting to tell you this.

414
00:33:32,000 --> 00:33:36,000
And then later on the system resets
itself and is amenable to being used

415
00:33:36,000 --> 00:33:40,000
again.  OK.  I should point out this
is an ion channel.

416
00:33:40,000 --> 00:33:44,000
This is a gated ion channel.
The Nobel Prize a couple of years

417
00:33:44,000 --> 00:33:49,000
ago was given to Rod MacKinnon and a
colleague whose name escapes me for

418
00:33:49,000 --> 00:33:53,000
getting the structure of these gated
ion channels.  And the notion is,

419
00:33:53,000 --> 00:33:57,000
I'll be an ion channel now.  The
notion is that in the membrane

420
00:33:57,000 --> 00:34:02,000
you're normally sitting something
like this.  OK?

421
00:34:02,000 --> 00:34:06,000
As an ion channel you get some kind
of stimulus.  The confirmation,

422
00:34:06,000 --> 00:34:10,000
and in the case of the neuron it's
going to be an electrical stimulus,

423
00:34:10,000 --> 00:34:14,000
that slight threshold depolarization.
And that is going to change the

424
00:34:14,000 --> 00:34:18,000
charge distribution on the proteins.
Those proteins will undergo some

425
00:34:18,000 --> 00:34:22,000
kind of conformational something and
they'll move like this and they'll

426
00:34:22,000 --> 00:34:26,000
open up the channel.
OK? And we know a bit more than

427
00:34:26,000 --> 00:34:30,000
that, but the notion
is exactly that.

428
00:34:30,000 --> 00:34:35,000
That changing the charge on the
proteins of an ion channel,

429
00:34:35,000 --> 00:34:40,000
of a gated ion channel changes the
confirmation of the protein and the

430
00:34:40,000 --> 00:34:46,000
channel opens up.
All right.  So I want to talk now,

431
00:34:46,000 --> 00:34:51,000
and I'll use the diagrams that I've
given you, about how you generate

432
00:34:51,000 --> 00:34:56,000
the resting potential and how you
generate the action potential in

433
00:34:56,000 --> 00:35:02,000
terms of the specific ions and the
specific channels that

434
00:35:02,000 --> 00:35:22,000
are being used.

435
00:35:22,000 --> 00:35:25,000
All right.  Channels that generate
the resting potential,

436
00:35:25,000 --> 00:35:28,000
and actually I don't need to write
this on the board because this is,

437
00:35:28,000 --> 00:35:31,000
these are going to be the last three
diagrams, diagrams four and five and

438
00:35:31,000 --> 00:35:35,000
six on the handout that
I gave you today.

439
00:35:35,000 --> 00:35:41,000
So how do you get this potential
difference across a plasma membrane?

440
00:35:41,000 --> 00:35:47,000
Well, in all cells, not just
neurons, in all cells it seems to be

441
00:35:47,000 --> 00:35:53,000
a function of something called a
sodium-potassium ATPase.

442
00:35:53,000 --> 00:36:00,000
And I will write this.  The
sodium-potassium ATPase is a pump.

443
00:36:00,000 --> 00:36:04,000
OK?  And its name kind of tells you
that.  The ATPase.

444
00:36:04,000 --> 00:36:09,000
It pumps sodium out of the cell and
it pumps potassium into the cell.

445
00:36:09,000 --> 00:36:13,000
And you can look in your book for a
bit more information about this.

446
00:36:13,000 --> 00:36:18,000
There is a fairly detailed
understanding of the mechanism by

447
00:36:18,000 --> 00:36:22,000
which it does this.
It's a very complex mechanism,

448
00:36:22,000 --> 00:36:27,000
but this gives you a gradient of
sodium, or gives you unequal

449
00:36:27,000 --> 00:36:32,000
distribution of sodium and potassium
ions across a plasma membrane.

450
00:36:32,000 --> 00:36:35,000
But, of course,
that doesn't necessarily give you a

451
00:36:35,000 --> 00:36:39,000
membrane potential.
That just gives you sodium on one

452
00:36:39,000 --> 00:36:42,000
side and potassium on the other side.
So how do you get the membrane

453
00:36:42,000 --> 00:36:46,000
potential?  Well,
this is very interesting because

454
00:36:46,000 --> 00:36:50,000
what you do is use some channels
that are open all the time.

455
00:36:50,000 --> 00:37:08,000
Now, what you've done with this

456
00:37:08,000 --> 00:37:12,000
sodium-potassium ATPase is to pump
potassium in and sodium out.

457
00:37:12,000 --> 00:37:16,000
So you've got high potassium on the
inside of the cell.

458
00:37:16,000 --> 00:37:20,000
If you open up the potassium
channels, the potassium is going to

459
00:37:20,000 --> 00:37:24,000
diffuse down its concentration
gradient and get out of the cell

460
00:37:24,000 --> 00:37:28,000
until there is some kind of charge
pull and you get an equilibrium

461
00:37:28,000 --> 00:37:32,000
because it's being pulled back and
pulled out and diffusing

462
00:37:32,000 --> 00:37:37,000
out with equal force.
The sodium channels are closed,

463
00:37:37,000 --> 00:37:41,000
so sodium is trapped outside the
cell.  And these three things,

464
00:37:41,000 --> 00:37:45,000
the sodium being pumped out, the
potassium pumped in,

465
00:37:45,000 --> 00:37:49,000
the open potassium channels and the
fact that there are no open sodium

466
00:37:49,000 --> 00:37:53,000
channels gives you this unequal
charge distribution across the

467
00:37:53,000 --> 00:37:57,000
membrane.  Now,
obviously there has to be some

468
00:37:57,000 --> 00:38:01,000
balance between this
sodium-potassium ATPase action

469
00:38:01,000 --> 00:38:06,000
and the channels.
Otherwise, you would not get a

470
00:38:06,000 --> 00:38:10,000
membrane potential.
But there is.  And the

471
00:38:10,000 --> 00:38:15,000
sodium-potassium ATPase pumps just
enough that you maintain this

472
00:38:15,000 --> 00:38:19,000
membrane potential.
OK.  So that's your resting

473
00:38:19,000 --> 00:38:24,000
potential.  How about your action
potential?  So your action potential

474
00:38:24,000 --> 00:38:28,000
involves another set of channels.
And the channels it involves are

475
00:38:28,000 --> 00:38:36,000
these gates --

476
00:38:36,000 --> 00:38:44,000
-- sodium channels.

477
00:38:44,000 --> 00:38:47,000
OK.  So in the region,
this is not animated, I'm going to

478
00:38:47,000 --> 00:38:50,000
tell you this.
In the region of the membrane where

479
00:38:50,000 --> 00:38:54,000
there is an action potential,
these gated sodium channels that are

480
00:38:54,000 --> 00:38:57,000
closed elsewhere open up and allow
sodium to move down its

481
00:38:57,000 --> 00:39:01,000
concentration gradient
into the cell.

482
00:39:01,000 --> 00:39:06,000
And they do it on a very mini scale,
OK, over micron or submicron domains

483
00:39:06,000 --> 00:39:11,000
of the cell membrane.
So you're getting this very little

484
00:39:11,000 --> 00:39:16,000
region of the membrane where these
sodium channels are opening and

485
00:39:16,000 --> 00:39:22,000
they're voltage-dependent opening
through this conformational change I

486
00:39:22,000 --> 00:39:27,000
belatedly demonstrated to you.
At the same time there is a set of

487
00:39:27,000 --> 00:39:33,000
channels, which are gated potassium
channels, and those are closed.

488
00:39:33,000 --> 00:39:40,000
There is a phase of repolarization

489
00:39:40,000 --> 00:39:44,000
that follows the action potential.
And during this the gated potassium

490
00:39:44,000 --> 00:39:49,000
channels open up,
potassium leaves the cell,

491
00:39:49,000 --> 00:39:54,000
and the gated sodium channels close
up.  And, as I mentioned,

492
00:39:54,000 --> 00:39:58,000
the ones in the vicinity of the
action potential,

493
00:39:58,000 --> 00:40:03,000
or the ones that have just opened
are now refractory for opening for

494
00:40:03,000 --> 00:40:08,000
another millisecond or so.
So in the repolarization you use

495
00:40:08,000 --> 00:40:13,000
potassium channels,
but a different set of potassium

496
00:40:13,000 --> 00:40:18,000
channels, a set of gated
potassium channels.

497
00:40:18,000 --> 00:40:26,000
And you're also using the

498
00:40:26,000 --> 00:40:30,000
sodium-potassium ATPase during this
time, because the sodium has to get

499
00:40:30,000 --> 00:40:35,000
out of the cell eventually.
OK?  And it will do so through the

500
00:40:35,000 --> 00:40:40,000
sodium-potassium ATPase exchange.
All right.  Here is a movie that

501
00:40:40,000 --> 00:40:44,000
will illustrate these different
points.  This is a diagram of an

502
00:40:44,000 --> 00:40:49,000
axon.  I've got in a loop so we'll
look at it a number of times.

503
00:40:49,000 --> 00:40:54,000
The membrane is shown in pink,
and these boxes are the ion channels

504
00:40:54,000 --> 00:40:58,000
that are initially closed.
And as the action potential moves

505
00:40:58,000 --> 00:41:03,000
along the axon they open up.
So here it comes again.

506
00:41:03,000 --> 00:41:08,000
They're closed.  And here they are
opening sequentially to allow the

507
00:41:08,000 --> 00:41:13,000
action potential to propagate.
Behind the action potential, take a

508
00:41:13,000 --> 00:41:18,000
look.  You'll see that they remain
closed for a while as it propagates.

509
00:41:18,000 --> 00:41:23,000
And then they eventually open up
and reset themselves.

510
00:41:23,000 --> 00:41:28,000
And so this is a very beautiful
example of an intracellular feedback

511
00:41:28,000 --> 00:41:33,000
loop, both a negative and
positive feedback loop.

512
00:41:33,000 --> 00:41:37,000
And so here you're regulating.
If you'd like to think of it in

513
00:41:37,000 --> 00:41:41,000
terms of regulating gene expression,
you're kind of doing it at a very

514
00:41:41,000 --> 00:41:45,000
mini level.  You're regulating gene
activity, certainly,

515
00:41:45,000 --> 00:41:50,000
or the outcome, the products of gene
activity.  This is a diagram above.

516
00:41:50,000 --> 00:41:54,000
I haven't dwelled on this.  You'll
see this more in section of the

517
00:41:54,000 --> 00:41:58,000
depolarization,
the action potential moving along.

518
00:41:58,000 --> 00:42:02,000
And you can depict that, as it's
often done, by showing,

519
00:42:02,000 --> 00:42:07,000
by plotting change in potential
against time.

520
00:42:07,000 --> 00:42:15,000
All right.

521
00:42:15,000 --> 00:42:19,000
Again, this is taken from your book.
Here's a diagram of the threshold

522
00:42:19,000 --> 00:42:24,000
potential, the action potential and
the repolarization.

523
00:42:24,000 --> 00:42:37,000
And I'm going to end off with a

524
00:42:37,000 --> 00:42:53,000
teaser for next lecture.
OK?  So that's what I want to say

525
00:42:53,000 --> 00:43:09,000
to you about the action potential.
I'm going to end off with a teaser

526
00:43:09,000 --> 00:43:26,000
for the next lecture.
These are two neurons.

527
00:43:26,000 --> 00:43:42,000
Each of the red dots, see the red
dots?  You probably cannot see them

528
00:43:42,000 --> 00:43:59,000
because there are so many.
They kind of look like a red blur.

529
00:43:59,000 --> 00:44:04,000
But, in fact, they're each red dots.
Each of those red dots is a

530
00:44:04,000 --> 00:44:09,000
connection between one of these two
neurons with another neuron.

531
00:44:09,000 --> 00:44:14,000
It is a synapse.  So we've talked
about moving the signal through the

532
00:44:14,000 --> 00:44:20,000
neuron, but now we are at the point
where the neuron,

533
00:44:20,000 --> 00:44:25,000
that axon needs to pass its signal
onto the next neuron.

534
00:44:25,000 --> 00:44:30,000
And it's going to do it through the
synapse, but it's not necessarily

535
00:44:30,000 --> 00:44:36,000
going to do it through one synapse
per cell or one synapse per axon.

536
00:44:36,000 --> 00:44:40,000
It's going to do it through up to 1,
00 or even more perhaps connections

537
00:44:40,000 --> 00:44:45,000
from each axon to the next one.
And what I'm going to talk to you

538
00:44:45,000 --> 00:44:49,000
about next time is how this is set
up.  We have a couple of minutes

539
00:44:49,000 --> 00:44:54,000
left so I will take you coming down
here and asking me questions,

540
00:44:54,000 --> 00:44:57,000
and I'll finish the class now.
Thank you.